Entry inhibitors
Encyclopedia
Entry inhibitors, also known as fusion inhibitors, are a class of antiretroviral drugs, used in combination therapy
for the treatment of HIV
infection. This class of drugs interferes with the binding, fusion and entry of an HIV virion to a human cell. By blocking this step in HIV's replication cycle, such agents slow the progression from HIV infection to AIDS
.
s involved in the HIV entry process.
Entry inhibitors work by interfering with one aspect of this process.
Combination therapy
Combination therapy or polytherapy is the use of more than one medication or other therapy. In contrast, monotherapy is any therapy which is taken by itself....
for the treatment of 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. This class of drugs interferes with the binding, fusion and entry of an HIV virion to a human cell. By blocking this step in HIV's replication cycle, such agents slow the progression from HIV infection to AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
.
Proteins
There are several key proteinProtein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s involved in the HIV entry process.
- CD4CD4CD4 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...
, a protein receptor found on the surface of helper T cells in the human immune system, also called CD4+ T cells - gp120Gp120Envelope glycoprotein GP120 is a glycoprotein exposed on the surface of the HIV envelope. The 120 in its name comes from its molecular weight of 120 kilodaltons...
, a protein on HIV surface that binds to the CD4 receptor - CCR5CCR5C-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...
, a second receptor found on the surface of CD4+ cells and macrophages, called a chemokineChemokineChemokines 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...
co-receptor - CXCR4CXCR4C-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 :...
, another chemokine co-receptor found on CD4+ cells - gp41Gp41gp41 is a subunit of the envelope protein complex of retroviruses, including Human immunodeficiency virus and Simian-Human immunodeficiency virus. This glycoprotein subunit remains non-covalently-bound to gp120, and provides the second step by which HIV enters the cell...
, a HIV protein, closely associated with gp120, that penetrates the cell membraneCell membraneThe cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
Binding, fusion, entry sequence
HIV entry into a human cells requires the following steps in sequence:- The binding of HIV surface protein gp120 to the CD4 receptor
- A conformational changeConformational changeA macromolecule is usually flexible and dynamic. It can change its shape in response to changes in its environment or other factors; each possible shape is called a conformation, and a transition between them is called a conformational change...
in gp120, which both increases its affinity for a coreceptor and exposes gp41Gp41gp41 is a subunit of the envelope protein complex of retroviruses, including Human immunodeficiency virus and Simian-Human immunodeficiency virus. This glycoprotein subunit remains non-covalently-bound to gp120, and provides the second step by which HIV enters the cell... - The binding of gp120 to a coreceptor either CCR5 or CXCR4
- The penetration of the cell membraneCell membraneThe cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
by gp41, which approximates the membrane of HIV and the T cell and promotes their fusion - The entry of the viral core into the cell
Entry inhibitors work by interfering with one aspect of this process.
Approved agents
- MaravirocMaravirocMaraviroc is an antiretroviral drug in the CCR5 receptor antagonist class used in the treatment of HIV infection. It is also classed as an entry inhibitor.-Mechanism of action:...
(Celsentri) binds to CCR5, preventing an interaction with gp120. It is also referred to as a "chemokine receptor antagonist" or a "CCR5 inhibitor." - EnfuvirtideEnfuvirtideEnfuvirtide is an HIV fusion inhibitor, the first of a novel class of antiretroviral drugs used in combination therapy for the treatment of HIV-1 infection. It is marketed under the trade name Fuzeon ....
(Fuzeon) binds to gp41 and interferes with its ability to approximate the two membranes. It is also referred to as a "fusion inhibitor."
Investigation / experimental agents
Other agents are under investigation for their ability to interact with the proteins involved in HIV entry and the possibility that they may serve as entry inhibitors.- TNX-355, a monoclonal antibody that binds CD4 and inhibits the binding of gp120
- PRO 140PRO 140PRO 140 is a humanized monoclonal antibody targeted against the CCR5 receptor found on T lymphocytes of the human immune system. It is being investigated as a potential therapy in the treatment of HIV infection....
, a monoclonal antibody that binds CCR5 - BMS-488043, a small molecule that interferes with the interaction of CD4 and gp120
- PlerixaforPlerixaforPlerixafor is an immunostimulant used in to multiply hematopoietic stem cells in cancer patients. The stem cells are subsequently transplanted back to the patient...
was being developed to interfere with interaction between HIV and CXCR4, but showed little useful antiviral activity in recent trials. - Epigallocatechin gallateEpigallocatechin gallateEpigallocatechin gallate , also known as epigallocatechin 3-gallate, is the ester of epigallocatechin and gallic acid, and is a type of catechin....
, a substance found in green teaGreen teaGreen tea is made solely from the leaves of Camellia sinensis that have undergone minimal oxidation during processing. Green tea originates from China and has become associated with many cultures throughout Asia. It has recently become more widespread in the West, where black tea is traditionally...
, appears to interact with gp120 as do several other theaflavinTheaflavinTheaflavin and its derivatives, known collectively as theaflavins, are antioxidant polyphenols that are formed from flavan-3-ols such as in tea leaves during the enzymatic oxidation of tea leaves, such as in black tea. Theaflavins are types of thearubigins, and are therefore reddish in color...
s. - VicrivirocVicrivirocVicriviroc, previously named SCH 417690 and SCH-D, is a pyrimidine CCR5 entry inhibitor of HIV-1. It was developed by the pharmaceutical company Schering-Plough. Merck decided to not pursue regulatory approval for use in treatment-experienced patients because the drug did not meet primary efficacy...
, similar to maraviroc, is currently undergoing clinical trials for FDA approval. - AplavirocAplavirocAplaviroc is a CCR5 entry inhibitor developed for the treatment of HIV infection. It is developed by GlaxoSmithKlineIn October 2005, all studies of aplaviroc were discontinued due to liver toxicity concerns...
, an agent similar to maraviroc and vicriroc. Clinical trials were halted in 2005 over concerns about the drug's safety. - b12 is an antibodyAntibodyAn antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
against HIV found in some long-term nonprogressorsLong-term nonprogressorsLong-term nonprogressors , less commonly called elite controllers, are rare individuals who are infected with HIV, but control the infection without antiretroviral therapy . Many of these patients have been HIV positive for 30 years without progressing to AIDS...
. It has been found to bind to gp120 at the exact region, or epitopeEpitopeAn epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that recognizes the epitope is called a paratope...
, where gp120 binds to CD4. b12 seems to serve as a natural entry inhibitor in some individuals. It is hoped that further study of b12 may lead to an effective HIV vaccine. - GriffithsinGriffithsinGriffithsin, is a protein isolated from the red algae Griffithsia. It has a 121-amino acid sequence. It has been shown in vitro to be a highly potent HIV entry inhibitor. It is currently being investigated as a potential microbicide for use in the prevention of the transmission of HIV...
, a substance derived from algae, appears to have entry inhibitor properties. - DCM205, is a small molecule based on L-chicoric acid, an integrase inhibitor. DCM205 has been reported to inactivate HIV-1 particles directly in vitro and is thought to act primarily as an entry inhibitor.
- CD4 specific Designed Ankyrin RepeatAnkyrin repeatThe ankyrin repeat is a 33-residue motif in proteins consisting of two alpha helices separated by loops, first discovered in signaling proteins in yeast Cdc10 and Drosophila Notch. Ankyrin repeats mediate protein–protein interactions and are among the most common structural motifs in known proteins...
Proteins (DARPinsDARPinDARPins are genetically engineered antibody mimetic proteins typically exhibiting highly specific and high-affinity target protein binding. They are derived from natural ankyrin proteins and consist of at least three, usually four or five repeat motifs of these proteins...
) potently block viral entry of diverse strains and are being developed and studied as potential microbicide candidates