Discovery and development of HIV protease inhibitors
Encyclopedia
Many major physiological processes depend on regulation of proteolytic
enzyme
activity and there can be dramatic consequences when equilibrium between an enzyme and its substrates is disturbed. In this prospective, the discovery of small-molecule ligands, like protease inhibitors, that can modulate catalytic activities has an enormous therapeutic effect. Hence, inhibition of the HIV protease
is one of the most important approaches for the therapeutic intervention in HIV
infection and their development is regarded as major success of structure-based drug design
. They are highly effective against HIV and have, since the 1990s, been a key component of anti-retroviral therapies for HIV/AIDS
.
that has two major species, HIV-1
which causes the majority of the epidemic
, and HIV-2
, a close relative whose distribution is concentrated in western Africa. HIV infection
was first described in 1981 in San Francisco and New York City. In 1985, HIV was identified as the causative agent of acquired immune deficiency syndrome (AIDS) and its complete genome
was immediately available. This knowledge paved the way for the development of selective
inhibitors
.
HIV-2 carries a slightly lower risk of transmission than HIV-1 and infection tends to progress more slowly to AIDS. In common usage HIV usually implies HIV-1.
HIV-1 protease is one of the best known aspartic proteases, and an attractive target for the treatment of AIDS.
After the discovery of HIV protease it only took 10 years for its first inhibitor to reach the market. The first reports of highly selective antagonists
against the HIV protease were revealed in 1987. Phase I trials of saquinavir
began in 1989 and it was the first HIV protease inhibitor to be approved for prescription use in 1995. Four months later, two other protease inhibitors, ritonavir
and indinavir
, were approved. In 2009, ten protease inhibitors have reached the market for treatment against HIV but one protease inhibitor, amprenavir, was withdrawn from the market in 2004.
HIV belongs to the class of viruses called retroviruses, which carry genetic information in the form of RNA
. HIV infects T cells that carry the CD4
antigen
on their surface. When HIV infects its target cell it requires fusion of the viral and cellular membranes. The first step is the interaction between envelope proteins of the virus (gp120, gp41) and specific host-cell surface receptors (e.g. CD4 receptor) on the target cell. Then the virus binds to the chemokine
coreceptors CXCR4
or CCR5
, resulting in conformational changes in the envelope proteins. This fusion creates a pore through which the viral capsid
enters the cell. Following entry into the cell the RNA of the virus is reverse-transcribed to DNA
by the first virally encoded enzyme
, the reverse transcriptase
. The viral DNA enters the nucleus
where it is integrated into the genetic material of the cell by the integrase
, a second virally encoded enzyme. Activation of the host cell leads to the transcription
of the viral DNA into mRNA. The mRNA is then translated into viral proteins and the third virally encoded enzyme, namely HIV protease, is required to cleave a viral polyprotein precursor into individual mature proteins. The viral RNA and viral proteins assemble at the surface of the cell into new virions
. The virions bud
from the cell and are released to infect other cells. All infected cells are eventually killed because of this extensive cell damage, from the destruction of the host's genetic system to the budding and release of virions.
by HIV protease. HIV protease inhibitors are peptide-like chemicals that competitively inhibit the action of the virus aspartyl protease. These drugs prevent proteolytic cleavage of HIV Gag and Pol polyproteins that include essential structural and enzymatic components of the virus. This prevents the conversion of HIV particles into their mature infectious form.
Protease inhibitors can alter adipocyte
metabolism causing lipodystrophy
, a common side effect
associated with the use of most HIV protease inhibitors. Many mechanisms have been proposed, for example inhibition of adipocyte differentiation
, triglyceride
accumulation and increased lipolysis
. Theories considering the effect of protease inhibitors on insulin-stimulated glucose uptake have also been linked to the lipodystrophic syndrome. It is possible that protease inhibitors can cause a decrease in insulin
-stimulated tyrosine
phosphorylation
of IRS-1, representing inhibition of early steps in insulin signaling. Decreased adiponectin
secretion and induced expression of interleukin-6 associated with HIV protease inhibitors may also contribute to inhibition of insulin-stimulated glucose uptake.
of the protease's actual substrates. A peptide linkage
consisting of –NH-CO- is replaced by an hydroxyethylen group (-CH2-CH(OH)-) which the protease is unable to cleave. HIV protease inhibitors fit the active site
of the HIV aspartic protease and were rationally designed utilizing knowledge of the aspartyl protease's mode of action
. The most promising transition state mimic was hydroxyethylamine which lead to the discovery of the first protease inhibitor, saquinavir
. Following that discovery, other HIV protease inhibitors were designed using the same principle.
monomers. Each monomer contributes an aspartic acid
residue that is essential for catalysis, Asp-25 and Asp-25´. The HIV protease has the sequence Asp-Thr
-Gly
, which is conserved among other mammalian aspartic protease enzymes. An extended beta-sheet
region on the monomers, known as the flap, constitutes in part the substrate binding site with the two aspartyl residues lying on the bottom of a hydrophobic
cavity. Each flexible flap contains three characteristic regions: side chains that extend outward (Met
46, Phe53), hydrophobic chains extending inward (Ile
47, Ile54), and a glycine rich region (Gly48, 49, 51, 52). Ile50 remains at the tip of the turn and when the enzyme is unliganded a water molecule makes hydrogen bonds to the backbone of Ile50 on each monomer.
HIV proteases catalyze the hydrolysis
of peptide bonds with high sequence selectivity and catalytic proficiency. The mechanism of the HIV protease shares many features with the rest of the aspartic protease family although the full detailed mechanism of this enzyme is not fully understood. The water molecule seems to play a role in the opening and closing of the flaps as well as increasing the affinity between enzyme and substrate. The aspartyl residues are involved in the hydrolysis of the peptide bonds. The preferred cleavage site for this enzyme is the N-terminal side of proline residues, especially between phenylalanine and proline or tyrosine and proline
.
hydroxyethylamine and was marketed in 1995. It is a transition state analogue of a native substrate of the protease. The observation that HIV-1 protease cleaves the sequences containing the dipeptides Tyr-Pro or Phe-Pro was the basic design criterion. Addition of the decahydroisoquinoline (DIQ) group was one of the most significant modifications that led to the discovery of saquinavir. This substituent improves aqueous solubility and potency by limiting the conformational freedom of the inhibitor.
Saquinavir is effective against both HIV-1 and HIV-2 and is usually well tolerated but high serum concentration is not achieved.
Ritonavir, a peptidomimetic HIV protease inhibitor, was marketed in 1996. It was designed to fit the C2-symmetry in the binding site of the protease. The developers of ritonavir, Abbott Laboratories
, started with compounds that were active against the virus but had poor bioavailability
. Some improvements were made, for example the terminal phenyl residues were removed and pyridyl
groups put instead to add water solubility. The final product of these improvements was ritonavir. Significant gastrointestinal side effects and a large pill burden are ritonavir's main drawbacks and is therefore not used as a single treatment. However, it is a strong inhibitor of the cytochrome P450 enzyme mediated metabolism and it is only used in a combination therapy with other protease inhibitors for pharmacokinetic boosting.
Indinavir, which is a peptidomimetic hydroxyethylene HIV protease inhibitor, reached the market in 1996. The design of indinavir was guided by molecular modeling and the X-ray
crystal structure
of the inhibited enzyme complex. The terminal phenyl constituents contribute hydrophobic binding to increase potency
. It is an analogue of the phenylalanine-proline cleavage site of the HIV Gag-polyprotein.
Nelfinavir
was the first protease inhibitor that was not peptidomimetic. In the design process of nelfinavir, an orally bioavailable and nonpeptidic inhibitor, iterative protein cocrystal structure analysis of peptidic inhibitors was used and parts of the inhibitors were replaced by nonpeptidic substituents. Nelfinavir contains a novel 2-methyl-3-hydroxybenzamide group, whereas
its carboxyl terminal contains the same DIQ group as saquinavir.
Nelfinavir was marketed in 1997 and was the first protease inhibitor to be indicated for pediatric AIDS.
Amprenavir reached the market in 1999. It is an N,N-disubstituded amino-sulfonamide
nonpeptide HIV protease inhibitor and shares some common features with previous protease inhibitors. It has a core similar to that of saquinavir but with different functional groups on both ends. On one end it has a tetrahydrofuran
carbamate group and on the other end is an isobutylphenyl sulfonamide with an added amide. This structure results in fewer chiral
centers, that makes it easier to synthesize and gives it enhanced aqueus solubility. That in turn gives better oral bioavailability. However, amprenavir was withdrawn from the market in 2004 since fosamprenavir, its prodrug
, proved superior in many aspects.
Lopinavir
was marketed in 2000 and was originally designed to diminish the interactions of the inhibitor with Val
82 of the HIV-1 protease, a residue that is often mutated
in the drug resistant
strains
of the virus. It is a peptidomimetic HIV protease inhbitor and its core is identical to that of ritonavir. Instead of the 5-thiazolyl
end group in ritonavir, lopinavir has a phenoxyacetyl group and the 2-isopropylthiazolyl group in ritonavir was replaced by a modified valine in which the amino terminal had a six-membered cyclic urea
attached.
Fosamprenavir
was marketed in 2003 and is a phosphoester prodrug that is
rapidly and extensively metabolized to amprenavir. The solubility and bioavailability is better than of amprenavir which results in reduced daily pill burden.
Atazanavir
was marketed in 2003 and is an azapeptide protease inhibitor designed to fit the C2-symmetry of the enzyme binding site. Atazanavir showed better resistant profiles than previous HIV protease inhibitors.
It is unique among the other protease inhibitors as it can only be absorbed
in an acidic environment.
Tipranavir
is a nonpeptidic HIV-1 protease inhibitor and reached the market in 2005. Unlike other HIV protease inhibitors on the market, tipranavir was developed from a nonpeptidic coumarin
template and its antiprotease activity was discovered by high-throughput screening
. This sulfonamide containing 5,6-dihydro-4-hydroxy-2-pyrone had emerged from screenings of 3-substituted coumarins and dihydropyrones. It possesses broad antiviral activity against multiple protease inhibitor resistant HIV-1.
Darunavir
reached the market in 2006 and is a nonpeptidic analogue of amprenavir, with a critical change at the terminal tetrahydrofuran (THF) group. Instead of a single THF group, darunavir contains two THF groups fused in the compound, to form a bis-THF moiety which makes it more effective than amprenavir. With this structural change, the stereochemistry
around the bis-THF moiety confers orientational changes, that allows for continued binding with the protease which has developed a resistance for amprenavir.
All the FDA approved protease inhibitors are listed below.
group on the core motif which forms a hydrogen bond with the carboxylic acid
on the Asp-25 and Asp-25´ residues in the binding site. Hydrogen bonds between the water molecule, which is linked to Ile50 and Ile50', and carbonyl
groups of the peptidomimetic inhibitors seem to connect them with the flap regions. On the other hand, on the nonpeptidic inhibitors, there is a proton acceptor which replaces the tetracoordinate
d water molecule and interacts directly with the two Ile50 residues on the flap of the enzyme. Specific pockets in the binding site of the HIV protease, often referred to as S1,S1',S2 and S2', recognize hydrophobic amino acids on natural substrates. The potency of inhibitors bearing hydrophobic groups complementing these areas is therefore increased. Some residues in the enzyme binding site are capable of forming hydrogen bonds with hydrophilic groups on the inhibitor, for example with the THF moieties on amprenavir and darunavir. Since darunavir has a bis-THF moiety, instead of a single THF moiety like on amprenavir, it can form more hydrogen bonds and increase binding energy
.
stability and conformational flexibility.
Over 100 single gene point mutations have been described, of which at least 26 are specific to protease inhibitors. Of these, there are about 15 primary or major mutations that are significant enough to change drug activity.
Many mutated residues have been found in HIV-1 protease which cause drug resistance, for example Leu33 changes to Ile, Val, or Phe; Val82 to Ala
, Phe, Leu, or Thr; Ile84 to Val; and Leu90 to Met. Different mutations affects different protease inhibitors. For instance, mutations at Leu90 evidently affect saquinavir and nelfinavir while indinavir activity is affected by mutations at Met46, Val82, and Ile84, and fosamprenavir is affected when Ile50 changes to Val and at Ile84. A combination of mutations can render high-level drug resistance but single mutations normally do not equate with drug resistance to protease inhibitors.
The mutations can be divided into primary mutations and secondary mutations. Primary mutations often have only a small effect on resistance. The chemical structures of most protease inhibitors are quite similar, so it is not surprising that some primary mutations lead simultaneously to resistance to multiple protease inhibitors. Cross-resistance
is one of the major problems of protease inhibitor treatment. Additional mutations emerging in the protease during continuous protease inhibitor therapy are commonly referred to as secondary mutations. This can lead to high-level protease inhibitor resistance.
There is no general strategy to tackle the problem of drug resistance. Researches directed towards development of new therapies to cure AIDS are focused on avoiding cross-resistance to drugs that are already on the market.
In 2006, GlaxoSmithKline
discontinued the phase II clinical development of brecanavir
, an investigational protease inhibitor for the treatment of HIV, due to insurmountable issues regarding formulation.
In the summer of 2009, GlaxoSmithKline and Concert Pharmaceuticals announced their collaboration to develop and commercialise deuterium
-containing medicines. One of them is CTP-518, a protease inhibitor for the treatment of HIV, expected to enter phase I clinical trials in the second half of 2009. CTP-518 is a novel HIV protease inhibitor developed by replacing certain key hydrogen atoms of atazanavir with deuterium. Pre-clinical studies have demonstrated that this modification fully retains the antiviral potency but can evidently slow hepatic metabolism and thereby increase the half life and plasma trough levels. CTP-518, therefore, has the potential to be the first HIV protease inhibitor to eliminate the need to co-dose with a boosting agent, such as ritonavir.
Proteolysis
Proteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion.-Purposes:Proteolysis is used by the cell for several purposes...
enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
activity and there can be dramatic consequences when equilibrium between an enzyme and its substrates is disturbed. In this prospective, the discovery of small-molecule ligands, like protease inhibitors, that can modulate catalytic activities has an enormous therapeutic effect. Hence, inhibition of the HIV protease
HIV-1 protease
HIV-1 protease is a retroviral aspartyl protease that is essential for the life-cycle of HIV, the retrovirus that causes AIDS.HIV PR cleaves newly synthesized polyproteins at the appropriate places to create the mature protein components of an infectious HIV virion...
is one of the most important approaches for the therapeutic intervention in HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
infection and their development is regarded as major success of structure-based drug design
Drug design
Drug design, also sometimes referred to as rational drug design or structure-based drug design, is the inventive process of finding new medications based on the knowledge of the biological target...
. They are highly effective against HIV and have, since the 1990s, been a key component of anti-retroviral therapies for HIV/AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
.
History
Human immunodeficiency virus (HIV) is a lentivirusLentivirus
Lentivirus is a genus of slow viruses of the Retroviridae family, characterized by a long incubation period...
that has two major species, HIV-1
Subtypes of HIV
One of the obstacles to treatment of the human immunodeficiency virus is its high genetic variability. HIV can be divided into two major types, HIV type 1 and HIV type 2 . HIV-1 is related to viruses found in chimpanzees and gorillas living in western Africa, while HIV-2 viruses are related to...
which causes the majority of the epidemic
Epidemic
In epidemiology, an epidemic , occurs when new cases of a certain disease, in a given human population, and during a given period, substantially exceed what is expected based on recent experience...
, and HIV-2
Subtypes of HIV
One of the obstacles to treatment of the human immunodeficiency virus is its high genetic variability. HIV can be divided into two major types, HIV type 1 and HIV type 2 . HIV-1 is related to viruses found in chimpanzees and gorillas living in western Africa, while HIV-2 viruses are related to...
, a close relative whose distribution is concentrated in western Africa. HIV infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
was first described in 1981 in San Francisco and New York City. In 1985, HIV was identified as the causative agent of acquired immune deficiency syndrome (AIDS) and its complete genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
was immediately available. This knowledge paved the way for the development of selective
Functional Selectivity
Functional selectivity is the ligand-dependent selectivity for certain signal transduction pathways in one and the same receptor. This can be present when a receptor has several possible signal transduction pathways...
inhibitors
Enzyme inhibitor
An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
.
HIV-2 carries a slightly lower risk of transmission than HIV-1 and infection tends to progress more slowly to AIDS. In common usage HIV usually implies HIV-1.
HIV-1 protease is one of the best known aspartic proteases, and an attractive target for the treatment of AIDS.
After the discovery of HIV protease it only took 10 years for its first inhibitor to reach the market. The first reports of highly selective antagonists
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
against the HIV protease were revealed in 1987. Phase I trials of saquinavir
Saquinavir
Saquinavir is an antiretroviral drug used in HIV therapy. It falls in the protease inhibitor class. Two formulations have been marketed:*a hard-gel capsule formulation of the mesylate, with trade name Invirase, which requires combination with ritonavir to increase the saquinavir bioavailability;*a...
began in 1989 and it was the first HIV protease inhibitor to be approved for prescription use in 1995. Four months later, two other protease inhibitors, ritonavir
Ritonavir
Ritonavir, with trade name Norvir , is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS....
and indinavir
Indinavir
Indinavir is a protease inhibitor used as a component of highly active antiretroviral therapy to treat HIV infection and AIDS.-History:...
, were approved. In 2009, ten protease inhibitors have reached the market for treatment against HIV but one protease inhibitor, amprenavir, was withdrawn from the market in 2004.
Life cycle of HIV
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
. HIV infects T cells that carry the CD4
CD4
CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...
antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
on their surface. When HIV infects its target cell it requires fusion of the viral and cellular membranes. The first step is the interaction between envelope proteins of the virus (gp120, gp41) and specific host-cell surface receptors (e.g. CD4 receptor) on the target cell. Then the virus binds to the chemokine
Chemokine
Chemokines are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines...
coreceptors CXCR4
CXCR4
C-X-C chemokine receptor type 4 also known as fusin or CD184 is a protein that in humans is encoded by the CXCR4 gene.- Function :...
or CCR5
CCR5
C-C chemokine receptor type 5, also known as CCR5, is a protein that in humans is encoded by the CCR5 gene. CCR5 is a member of the beta chemokine receptors family of integral membrane proteins...
, resulting in conformational changes in the envelope proteins. This fusion creates a pore through which the viral capsid
Capsid
A capsid is the protein shell of a virus. It consists of several oligomeric structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or may not correspond to individual proteins, are called capsomeres. The capsid encloses the genetic...
enters the cell. Following entry into the cell the RNA of the virus is reverse-transcribed to DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
by the first virally encoded enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
, the reverse transcriptase
Reverse transcriptase
In the fields of molecular biology and biochemistry, a reverse transcriptase, also known as RNA-dependent DNA polymerase, is a DNA polymerase enzyme that transcribes single-stranded RNA into single-stranded DNA. It also helps in the formation of a double helix DNA once the RNA has been reverse...
. The viral DNA enters the nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
where it is integrated into the genetic material of the cell by the integrase
Integrase
Retroviral integrase is an enzyme produced by a retrovirus that enables its genetic material to be integrated into the DNA of the infected cell...
, a second virally encoded enzyme. Activation of the host cell leads to the transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
of the viral DNA into mRNA. The mRNA is then translated into viral proteins and the third virally encoded enzyme, namely HIV protease, is required to cleave a viral polyprotein precursor into individual mature proteins. The viral RNA and viral proteins assemble at the surface of the cell into new virions
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
. The virions bud
Budding
Budding is a form of asexual reproduction in which a new organism grows on another one. The new organism remains attached as it grows, separating from the parent organism only when it is mature. Since the reproduction is asexual, the newly created organism is a clone and is genetically identical...
from the cell and are released to infect other cells. All infected cells are eventually killed because of this extensive cell damage, from the destruction of the host's genetic system to the budding and release of virions.
Mechanism of action
There are several steps in the HIV life cycle that may be interfered with, thus stopping the replication of the virus. A very critical step is the proteolytic cleavage of the polypeptide precursors into mature enzymes and structural proteins catalyzedCatalysis
Catalysis is the change in rate of a chemical reaction due to the participation of a substance called a catalyst. Unlike other reagents that participate in the chemical reaction, a catalyst is not consumed by the reaction itself. A catalyst may participate in multiple chemical transformations....
by HIV protease. HIV protease inhibitors are peptide-like chemicals that competitively inhibit the action of the virus aspartyl protease. These drugs prevent proteolytic cleavage of HIV Gag and Pol polyproteins that include essential structural and enzymatic components of the virus. This prevents the conversion of HIV particles into their mature infectious form.
Protease inhibitors can alter adipocyte
Adipocyte
However, in some reports and textbooks, the number of fat cell increased in childhood and adolescence. The total number is constant in both obese and lean adult...
metabolism causing lipodystrophy
Lipodystrophy
Lipodystrophy is a medical condition characterized by abnormal or degenerative conditions of the body's adipose tissue. A more specific term, lipoatrophy is used when describing the loss of fat from one area...
, a common side effect
Adverse effect
In medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as surgery.An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. If it results from an unsuitable or incorrect dosage or...
associated with the use of most HIV protease inhibitors. Many mechanisms have been proposed, for example inhibition of adipocyte differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
, triglyceride
Triglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
accumulation and increased lipolysis
Lipolysis
Lipolysis is the breakdown of lipids and involves the hydrolysis of triglycerides into free fatty acids followed by further degradation into acetyl units by beta oxidation. The process produces Ketones, which are found in large quantities in ketosis, a metabolic state that occurs when the liver...
. Theories considering the effect of protease inhibitors on insulin-stimulated glucose uptake have also been linked to the lipodystrophic syndrome. It is possible that protease inhibitors can cause a decrease in insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
-stimulated tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
phosphorylation
Protein phosphorylation
Protein phosphorylation is a post-translational modification of proteins in which a serine, a threonine or a tyrosine residue is phosphorylated by a protein kinase by the addition of a covalently bound phosphate group. Regulation of proteins by phosphorylation is one of the most common modes of...
of IRS-1, representing inhibition of early steps in insulin signaling. Decreased adiponectin
Adiponectin
Adiponectin is a protein which in humans is encoded by the ADIPOQ gene.- Structure :...
secretion and induced expression of interleukin-6 associated with HIV protease inhibitors may also contribute to inhibition of insulin-stimulated glucose uptake.
Design
Protease inhibitors were designed to mimic the transition stateTransition state
The transition state of a chemical reaction is a particular configuration along the reaction coordinate. It is defined as the state corresponding to the highest energy along this reaction coordinate. At this point, assuming a perfectly irreversible reaction, colliding reactant molecules will always...
of the protease's actual substrates. A peptide linkage
Peptide bond
This article is about the peptide link found within biological molecules, such as proteins. A similar article for synthetic molecules is being created...
consisting of –NH-CO- is replaced by an hydroxyethylen group (-CH2-CH(OH)-) which the protease is unable to cleave. HIV protease inhibitors fit the active site
Active site
In biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...
of the HIV aspartic protease and were rationally designed utilizing knowledge of the aspartyl protease's mode of action
Mechanism of action
In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect...
. The most promising transition state mimic was hydroxyethylamine which lead to the discovery of the first protease inhibitor, saquinavir
Saquinavir
Saquinavir is an antiretroviral drug used in HIV therapy. It falls in the protease inhibitor class. Two formulations have been marketed:*a hard-gel capsule formulation of the mesylate, with trade name Invirase, which requires combination with ritonavir to increase the saquinavir bioavailability;*a...
. Following that discovery, other HIV protease inhibitors were designed using the same principle.
Binding site
The HIV protease is a C2-symmetric homodimeric enzyme consisting of two 99 amino acidAmino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
monomers. Each monomer contributes an aspartic acid
Aspartic acid
Aspartic acid is an α-amino acid with the chemical formula HOOCCHCH2COOH. The carboxylate anion, salt, or ester of aspartic acid is known as aspartate. The L-isomer of aspartate is one of the 20 proteinogenic amino acids, i.e., the building blocks of proteins...
residue that is essential for catalysis, Asp-25 and Asp-25´. The HIV protease has the sequence Asp-Thr
Threonine
Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...
-Gly
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
, which is conserved among other mammalian aspartic protease enzymes. An extended beta-sheet
Beta sheet
The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...
region on the monomers, known as the flap, constitutes in part the substrate binding site with the two aspartyl residues lying on the bottom of a hydrophobic
Hydrophobe
In chemistry, hydrophobicity is the physical property of a molecule that is repelled from a mass of water....
cavity. Each flexible flap contains three characteristic regions: side chains that extend outward (Met
Methionine
Methionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...
46, Phe53), hydrophobic chains extending inward (Ile
Isoleucine
Isoleucine is an α-amino acid with the chemical formula HO2CCHCHCH2CH3. It is an essential amino acid, which means that humans cannot synthesize it, so it must be ingested. Its codons are AUU, AUC and AUA....
47, Ile54), and a glycine rich region (Gly48, 49, 51, 52). Ile50 remains at the tip of the turn and when the enzyme is unliganded a water molecule makes hydrogen bonds to the backbone of Ile50 on each monomer.
HIV proteases catalyze the hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
of peptide bonds with high sequence selectivity and catalytic proficiency. The mechanism of the HIV protease shares many features with the rest of the aspartic protease family although the full detailed mechanism of this enzyme is not fully understood. The water molecule seems to play a role in the opening and closing of the flaps as well as increasing the affinity between enzyme and substrate. The aspartyl residues are involved in the hydrolysis of the peptide bonds. The preferred cleavage site for this enzyme is the N-terminal side of proline residues, especially between phenylalanine and proline or tyrosine and proline
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
.
Development
The first HIV protease inhibitor, saquinavir, is a peptidomimeticPeptidomimetic
A peptidomimetic is a small protein-like chain designed to mimic a peptide. They typically arise either from modification of an existing peptide, or by designing similar systems that mimic peptides, such as peptoids and β-peptides...
hydroxyethylamine and was marketed in 1995. It is a transition state analogue of a native substrate of the protease. The observation that HIV-1 protease cleaves the sequences containing the dipeptides Tyr-Pro or Phe-Pro was the basic design criterion. Addition of the decahydroisoquinoline (DIQ) group was one of the most significant modifications that led to the discovery of saquinavir. This substituent improves aqueous solubility and potency by limiting the conformational freedom of the inhibitor.
Saquinavir is effective against both HIV-1 and HIV-2 and is usually well tolerated but high serum concentration is not achieved.
Ritonavir, a peptidomimetic HIV protease inhibitor, was marketed in 1996. It was designed to fit the C2-symmetry in the binding site of the protease. The developers of ritonavir, Abbott Laboratories
Abbott Laboratories
Abbott Laboratories is an American-based global, diversified pharmaceuticals and health care products company. It has 90,000 employees and operates in over 130 countries. The company headquarters are in Abbott Park, North Chicago, Illinois. The company was founded by Chicago physician, Dr....
, started with compounds that were active against the virus but had poor bioavailability
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
. Some improvements were made, for example the terminal phenyl residues were removed and pyridyl
Pyridine
Pyridine is a basic heterocyclic organic compound with the chemical formula C5H5N. It is structurally related to benzene, with one C-H group replaced by a nitrogen atom...
groups put instead to add water solubility. The final product of these improvements was ritonavir. Significant gastrointestinal side effects and a large pill burden are ritonavir's main drawbacks and is therefore not used as a single treatment. However, it is a strong inhibitor of the cytochrome P450 enzyme mediated metabolism and it is only used in a combination therapy with other protease inhibitors for pharmacokinetic boosting.
Indinavir, which is a peptidomimetic hydroxyethylene HIV protease inhibitor, reached the market in 1996. The design of indinavir was guided by molecular modeling and the X-ray
X-ray
X-radiation is a form of electromagnetic radiation. X-rays have a wavelength in the range of 0.01 to 10 nanometers, corresponding to frequencies in the range 30 petahertz to 30 exahertz and energies in the range 120 eV to 120 keV. They are shorter in wavelength than UV rays and longer than gamma...
crystal structure
Crystal structure
In mineralogy and crystallography, crystal structure is a unique arrangement of atoms or molecules in a crystalline liquid or solid. A crystal structure is composed of a pattern, a set of atoms arranged in a particular way, and a lattice exhibiting long-range order and symmetry...
of the inhibited enzyme complex. The terminal phenyl constituents contribute hydrophobic binding to increase potency
Potency (pharmacology)
In the field of pharmacology, potency is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity. A highly potent drug evokes a larger response at low concentrations, while a drug of lower potency evokes a small response at low concentrations...
. It is an analogue of the phenylalanine-proline cleavage site of the HIV Gag-polyprotein.
Nelfinavir
Nelfinavir
Nelfinavir is an antiretroviral drug used in the treatment of the human immunodeficiency virus . Nelfinavir belongs to the class of drugs known as protease inhibitors and like other PIs is generally used in combination with other antiretroviral drugs.Nelfinavir mesylate is a potent and orally...
was the first protease inhibitor that was not peptidomimetic. In the design process of nelfinavir, an orally bioavailable and nonpeptidic inhibitor, iterative protein cocrystal structure analysis of peptidic inhibitors was used and parts of the inhibitors were replaced by nonpeptidic substituents. Nelfinavir contains a novel 2-methyl-3-hydroxybenzamide group, whereas
its carboxyl terminal contains the same DIQ group as saquinavir.
Nelfinavir was marketed in 1997 and was the first protease inhibitor to be indicated for pediatric AIDS.
Amprenavir reached the market in 1999. It is an N,N-disubstituded amino-sulfonamide
Sulfonamide (chemistry)
In chemistry, the sulfonamide functional group is -S2-NH2, a sulfonyl group connected to an amine group.A sulfonamide is a compound that contains this group. The general formula is RSO2NH2, where R is some organic group. For example, "methanesulfonamide" is CH3SO2NH2...
nonpeptide HIV protease inhibitor and shares some common features with previous protease inhibitors. It has a core similar to that of saquinavir but with different functional groups on both ends. On one end it has a tetrahydrofuran
Tetrahydrofuran
Tetrahydrofuran is a colorless, water-miscible organic liquid with low viscosity at standard temperature and pressure. This heterocyclic compound has the chemical formula 4O. As one of the most polar ethers with a wide liquid range, it is a useful solvent. Its main use, however, is as a precursor...
carbamate group and on the other end is an isobutylphenyl sulfonamide with an added amide. This structure results in fewer chiral
Chirality (chemistry)
A chiral molecule is a type of molecule that lacks an internal plane of symmetry and thus has a non-superimposable mirror image. The feature that is most often the cause of chirality in molecules is the presence of an asymmetric carbon atom....
centers, that makes it easier to synthesize and gives it enhanced aqueus solubility. That in turn gives better oral bioavailability. However, amprenavir was withdrawn from the market in 2004 since fosamprenavir, its prodrug
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
, proved superior in many aspects.
Lopinavir
Lopinavir
Lopinavir is an antiretroviral of the protease inhibitor class. It is used as a fixed-dose combination with another protease inhibitor, ritonavir, under the trade names Kaletra and Aluvia ....
was marketed in 2000 and was originally designed to diminish the interactions of the inhibitor with Val
Valine
Valine is an α-amino acid with the chemical formula HO2CCHCH2. L-Valine is one of 20 proteinogenic amino acids. Its codons are GUU, GUC, GUA, and GUG. This essential amino acid is classified as nonpolar...
82 of the HIV-1 protease, a residue that is often mutated
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
in the drug resistant
Drug resistance
Drug resistance is the reduction in effectiveness of a drug such as an antimicrobial or an antineoplastic in curing a disease or condition. When the drug is not intended to kill or inhibit a pathogen, then the term is equivalent to dosage failure or drug tolerance. More commonly, the term is used...
strains
Strain (biology)
In biology, a strain is a low-level taxonomic rank used in three related ways.-Microbiology and virology:A strain is a genetic variant or subtype of a micro-organism . For example, a "flu strain" is a certain biological form of the influenza or "flu" virus...
of the virus. It is a peptidomimetic HIV protease inhbitor and its core is identical to that of ritonavir. Instead of the 5-thiazolyl
Thiazole
Thiazole, or 1,3-thiazole, is a heterocyclic compound that contains both sulfur and nitrogen; the term 'thiazole' also refers to a large family of derivatives. Thiazole itself is a pale yellow liquid with a pyridine-like odor and the molecular formula C3H3NS...
end group in ritonavir, lopinavir has a phenoxyacetyl group and the 2-isopropylthiazolyl group in ritonavir was replaced by a modified valine in which the amino terminal had a six-membered cyclic urea
Urea
Urea or carbamide is an organic compound with the chemical formula CO2. The molecule has two —NH2 groups joined by a carbonyl functional group....
attached.
Fosamprenavir
Fosamprenavir
Fosamprenavir , under the trade names Lexiva and Telzir is a pro-drug of the protease inhibitor and antiretroviral drug amprenavir. The FDA approved it October 20, 2003, while the EMEA approved it on July 12, 2004...
was marketed in 2003 and is a phosphoester prodrug that is
rapidly and extensively metabolized to amprenavir. The solubility and bioavailability is better than of amprenavir which results in reduced daily pill burden.
Atazanavir
Atazanavir
Atazanavir, marketed under the trade name Reyataz by Bristol Myers, is an antiretroviral drug of the protease inhibitor class...
was marketed in 2003 and is an azapeptide protease inhibitor designed to fit the C2-symmetry of the enzyme binding site. Atazanavir showed better resistant profiles than previous HIV protease inhibitors.
It is unique among the other protease inhibitors as it can only be absorbed
Absorption (Pharmacokinetics)
In pharmacology , absorption is the movement of a drug into the bloodstream.Absorption involves several phases...
in an acidic environment.
Tipranavir
Tipranavir
Tipranavir, or tipranavir disodium, is a nonpeptidic protease inhibitor manufactured by Boehringer-Ingelheim under the trade name Aptivus...
is a nonpeptidic HIV-1 protease inhibitor and reached the market in 2005. Unlike other HIV protease inhibitors on the market, tipranavir was developed from a nonpeptidic coumarin
Coumarin
Coumarin is a fragrant chemical compound in the benzopyrone chemical class, found in many plants, notably in high concentration in the tonka bean , vanilla grass , sweet woodruff , mullein , sweet grass , cassia cinnamon and sweet clover...
template and its antiprotease activity was discovered by high-throughput screening
High-throughput screening
High-throughput screening is a method for scientific experimentation especially used in drug discovery and relevant to the fields of biology and chemistry. Using robotics, data processing and control software, liquid handling devices, and sensitive detectors, High-Throughput Screening allows a...
. This sulfonamide containing 5,6-dihydro-4-hydroxy-2-pyrone had emerged from screenings of 3-substituted coumarins and dihydropyrones. It possesses broad antiviral activity against multiple protease inhibitor resistant HIV-1.
Darunavir
Darunavir
Darunavir is a drug used to treat HIV infection. It is in the protease inhibitor class. Prezista is an OARAC recommended treatment option for treatment-naïve and treatment-experienced adults and adolescents. Developed by pharmaceutical company Tibotec, darunavir is named after Arun K...
reached the market in 2006 and is a nonpeptidic analogue of amprenavir, with a critical change at the terminal tetrahydrofuran (THF) group. Instead of a single THF group, darunavir contains two THF groups fused in the compound, to form a bis-THF moiety which makes it more effective than amprenavir. With this structural change, the stereochemistry
Stereochemistry
Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms within molecules. An important branch of stereochemistry is the study of chiral molecules....
around the bis-THF moiety confers orientational changes, that allows for continued binding with the protease which has developed a resistance for amprenavir.
All the FDA approved protease inhibitors are listed below.
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| Saquinavir Saquinavir Saquinavir is an antiretroviral drug used in HIV therapy. It falls in the protease inhibitor class. Two formulations have been marketed:*a hard-gel capsule formulation of the mesylate, with trade name Invirase, which requires combination with ritonavir to increase the saquinavir bioavailability;*a... |
Ritonavir Ritonavir Ritonavir, with trade name Norvir , is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS.... |
Indinavir Indinavir Indinavir is a protease inhibitor used as a component of highly active antiretroviral therapy to treat HIV infection and AIDS.-History:... |
Nelfinavir Nelfinavir Nelfinavir is an antiretroviral drug used in the treatment of the human immunodeficiency virus . Nelfinavir belongs to the class of drugs known as protease inhibitors and like other PIs is generally used in combination with other antiretroviral drugs.Nelfinavir mesylate is a potent and orally... |
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| Amprenavir | Lopinavir Lopinavir Lopinavir is an antiretroviral of the protease inhibitor class. It is used as a fixed-dose combination with another protease inhibitor, ritonavir, under the trade names Kaletra and Aluvia .... |
Fosamprenavir Fosamprenavir Fosamprenavir , under the trade names Lexiva and Telzir is a pro-drug of the protease inhibitor and antiretroviral drug amprenavir. The FDA approved it October 20, 2003, while the EMEA approved it on July 12, 2004... |
Atazanavir Atazanavir Atazanavir, marketed under the trade name Reyataz by Bristol Myers, is an antiretroviral drug of the protease inhibitor class... |
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| Tipranavir Tipranavir Tipranavir, or tipranavir disodium, is a nonpeptidic protease inhibitor manufactured by Boehringer-Ingelheim under the trade name Aptivus... |
Darunavir Darunavir Darunavir is a drug used to treat HIV infection. It is in the protease inhibitor class. Prezista is an OARAC recommended treatment option for treatment-naïve and treatment-experienced adults and adolescents. Developed by pharmaceutical company Tibotec, darunavir is named after Arun K... |
Structure-activity relationship
All the HIV protease inhibitors on the market contain a central core motif consisting of a hydroxyethylen scaffold, with the only exception being the central core of tipranavir, which is based on a coumarin scaffold. A very important group on the HIV protease inhibitors is a hydroxylHydroxyl
A hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...
group on the core motif which forms a hydrogen bond with the carboxylic acid
Carboxylic acid
Carboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...
on the Asp-25 and Asp-25´ residues in the binding site. Hydrogen bonds between the water molecule, which is linked to Ile50 and Ile50', and carbonyl
Carbonyl
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups....
groups of the peptidomimetic inhibitors seem to connect them with the flap regions. On the other hand, on the nonpeptidic inhibitors, there is a proton acceptor which replaces the tetracoordinate
Tetracoordinate
Tetracoordinate in coordination chemistry generally refers to four ligands or atomic attachments to a single metal centre. Tetracoordinate species can form tetrahedral, square planar or pyramidal geometries. This is usually dictated by lone electron pairs on the metal centre....
d water molecule and interacts directly with the two Ile50 residues on the flap of the enzyme. Specific pockets in the binding site of the HIV protease, often referred to as S1,S1',S2 and S2', recognize hydrophobic amino acids on natural substrates. The potency of inhibitors bearing hydrophobic groups complementing these areas is therefore increased. Some residues in the enzyme binding site are capable of forming hydrogen bonds with hydrophilic groups on the inhibitor, for example with the THF moieties on amprenavir and darunavir. Since darunavir has a bis-THF moiety, instead of a single THF moiety like on amprenavir, it can form more hydrogen bonds and increase binding energy
Binding energy
Binding energy is the mechanical energy required to disassemble a whole into separate parts. A bound system typically has a lower potential energy than its constituent parts; this is what keeps the system together—often this means that energy is released upon the creation of a bound state...
.
Resistance
Mutations that code for alterations of the conformational shape facilitate resistance of HIV to protease inhibitors. The locations of these mutations are primarily in the active site of the HIV protease enzyme as well as outside of the active site. Active site mutations have been shown to directly change the interactions of the inhibitors with the protease whilst non-active site mutations are considered to affect by other mechanisms, like influencing dimerProtein dimer
In biochemistry, a dimer is a macromolecular complex formed by two, usually non-covalently bound, macromolecules like proteins or nucleic acids...
stability and conformational flexibility.
Over 100 single gene point mutations have been described, of which at least 26 are specific to protease inhibitors. Of these, there are about 15 primary or major mutations that are significant enough to change drug activity.
Many mutated residues have been found in HIV-1 protease which cause drug resistance, for example Leu33 changes to Ile, Val, or Phe; Val82 to Ala
Alanine
Alanine is an α-amino acid with the chemical formula CH3CHCOOH. The L-isomer is one of the 20 amino acids encoded by the genetic code. Its codons are GCU, GCC, GCA, and GCG. It is classified as a nonpolar amino acid...
, Phe, Leu, or Thr; Ile84 to Val; and Leu90 to Met. Different mutations affects different protease inhibitors. For instance, mutations at Leu90 evidently affect saquinavir and nelfinavir while indinavir activity is affected by mutations at Met46, Val82, and Ile84, and fosamprenavir is affected when Ile50 changes to Val and at Ile84. A combination of mutations can render high-level drug resistance but single mutations normally do not equate with drug resistance to protease inhibitors.
The mutations can be divided into primary mutations and secondary mutations. Primary mutations often have only a small effect on resistance. The chemical structures of most protease inhibitors are quite similar, so it is not surprising that some primary mutations lead simultaneously to resistance to multiple protease inhibitors. Cross-resistance
Cross-resistance
Cross-resistance is the tolerance to a usually toxic substance as a result of exposure to a similarly acting substance. It is a phenomenon affecting e.g. pesticides and antibiotics. As an example rifabutin and rifampin cross react in the treatment of tuberculosis. This sort of resistance is also...
is one of the major problems of protease inhibitor treatment. Additional mutations emerging in the protease during continuous protease inhibitor therapy are commonly referred to as secondary mutations. This can lead to high-level protease inhibitor resistance.
There is no general strategy to tackle the problem of drug resistance. Researches directed towards development of new therapies to cure AIDS are focused on avoiding cross-resistance to drugs that are already on the market.
Current status
In November 2009 darunavir was still the most recent HIV protease inhibitor to reach the market.In 2006, GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...
discontinued the phase II clinical development of brecanavir
Brecanavir
Brecanavir is a protease inhibitor which has been studied for the treatment of HIV.On December 2006, its developer, GlaxoSmithKline discontinued further development because of insurmountable issues regarding formulation....
, an investigational protease inhibitor for the treatment of HIV, due to insurmountable issues regarding formulation.
In the summer of 2009, GlaxoSmithKline and Concert Pharmaceuticals announced their collaboration to develop and commercialise deuterium
Deuterium
Deuterium, also called heavy hydrogen, is one of two stable isotopes of hydrogen. It has a natural abundance in Earth's oceans of about one atom in of hydrogen . Deuterium accounts for approximately 0.0156% of all naturally occurring hydrogen in Earth's oceans, while the most common isotope ...
-containing medicines. One of them is CTP-518, a protease inhibitor for the treatment of HIV, expected to enter phase I clinical trials in the second half of 2009. CTP-518 is a novel HIV protease inhibitor developed by replacing certain key hydrogen atoms of atazanavir with deuterium. Pre-clinical studies have demonstrated that this modification fully retains the antiviral potency but can evidently slow hepatic metabolism and thereby increase the half life and plasma trough levels. CTP-518, therefore, has the potential to be the first HIV protease inhibitor to eliminate the need to co-dose with a boosting agent, such as ritonavir.
See also
- Antiretroviral drugAntiretroviral drugAntiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. When several such drugs, typically three or four, are taken in combination, the approach is known as Highly Active Antiretroviral Therapy, or HAART...
- Reverse transcriptase inhibitorReverse transcriptase inhibitorReverse-transcriptase inhibitors are a class of antiretroviral drug used to treat HIV infection, tumors, and cancer. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase enzyme that retroviruses need to reproduce.-Mechanism:...
- Integrase inhibitorIntegrase inhibitorIntegrase inhibitors are a class of antiretroviral drug designed to block the action of integrase, a viral enzyme that inserts the viral genome into the DNA of the host cell. Since integration is a vital step in retroviral replication, blocking it can halt further spread of the virus...
- Entry inhibitor
- Discovery and development of non-nucleoside reverse transcriptase inhibitorsDiscovery and development of non-nucleoside reverse transcriptase inhibitorsNon-nucleoside reverse-transcriptase inhibitors are antiretroviral drugs used in the treatment of human immunodeficiency virus . NNRTIs inhibit reverse transcriptase , an enzyme that controls the replication of the genetic material of HIV...