Entry inhibitors, also known as fusion inhibitors, are a class of

antiviral drug Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Antiviral drugs are a class of antimicrobials ...

s that prevent a

virus A virus is a submicroscopic infectious agent that replicates only inside the living Cell (biology), cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Viruses are ...

from entering a

cell Cell most often refers to: * Cell (biology), the functional basic unit of life * Cellphone, a phone connected to a cellular network * Clandestine cell, a penetration-resistant form of a secret or outlawed organization * Electrochemical cell, a de ...

, for example, by blocking a

receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...

. Entry inhibitors are used to treat conditions such as

HIV The human immunodeficiency viruses (HIV) are two species of '' Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the im ...

and

hepatitis D Hepatitis D is a type of viral hepatitis caused by the hepatitis delta virus (HDV). HDV is one of five known hepatitis viruses: A, B, C, D, and E. HDV is considered to be a satellite (a type of subviral agent) because it can propagate only in ...

HIV entry

They are used in

combination therapy In mathematics, a combination is a selection of items from a set that has distinct members, such that the order of selection does not matter (unlike permutations). For example, given three fruits, say an apple, an orange and a pear, there are ...

for the treatment of

infection. This class of drugs interferes with the binding, fusion and entry of an HIV

virion A virion (plural, ''viria'' or ''virions'') is an inert virus particle capable of invading a Cell (biology), cell. Upon entering the cell, the virion disassembles and the genetic material from the virus takes control of the cell infrastructure, t ...

to a human cell. By blocking this step in HIV's replication cycle, such agents slow the progression from HIV infection to

AIDS The HIV, human immunodeficiency virus (HIV) is a retrovirus that attacks the immune system. Without treatment, it can lead to a spectrum of conditions including acquired immunodeficiency syndrome (AIDS). It is a Preventive healthcare, pr ...

Proteins

There are several key

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

s involved in the HIV entry process. *

CD4 In molecular biology, CD4 (cluster of differentiation 4) is a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). CD4 is found on the surface of immune cells such as helper T cells, monocytes, macrophages, and dendritic c ...

, a protein receptor found on the surface of

helper T cell The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...

s in the human immune system, also called CD4+ T cells *

gp120 Envelope glycoprotein GP120 (or gp120) is a glycoprotein exposed on the surface of the HIV envelope. It was discovered by Professors Tun-Hou Lee and Myron "Max" Essex of the Harvard School of Public Health in 1984. The 120 in its name comes f ...

, a protein on HIV surface that binds to the CD4 receptor *

CCR5 C-C chemokine receptor type 5, also known as CCR5 or CD195, is a protein on the surface of white blood cells that is involved in the immune system as it acts as a receptor for chemokines. In humans, the ''CCR5'' gene that encodes the CCR5 p ...

, a second receptor found on the surface of CD4+ cells and macrophages, called a

chemokine Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addit ...

co-receptor *

CXCR4 C-X-C chemokine receptor type 4 (CXCR-4) also known as fusin or CD184 (cluster of differentiation 184) is a protein that in humans is encoded by the ''CXCR4'' gene. The protein is a CXC chemokine receptor. Function CXCR-4 is an alpha- chemo ...

, another chemokine co-receptor found on CD4+ cells *

gp41 Gp41 also known as glycoprotein 41 is a subunit of the envelope protein complex of retroviruses, including human immunodeficiency virus (HIV). Gp41 is a transmembrane protein that contains several sites within its ectodomain that are required fo ...

, an HIV protein, closely associated with

, that penetrates the

cell membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...

Binding, fusion, entry sequence

HIV entry into a human cell requires the following steps in sequence. # The binding of HIV surface protein

to the CD4 receptor # A

conformational change In biochemistry, a conformational change is a change in the shape of a macromolecule, often induced by environmental factors. A macromolecule is usually flexible and dynamic. Its shape can change in response to changes in its environment or othe ...

, which both increases its affinity for a co-receptor and exposes

# The binding of

to a

co-receptor A co-receptor is a cell surface receptor that binds a signalling molecule in addition to a primary receptor in order to facilitate Ligand (biochemistry), ligand recognition and initiate biological processes, such as entry of a pathogen into a host ...

''either'' CCR5 or CXCR4 # The penetration of the

by gp41, which approximates the membrane of HIV and the

T cell T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell ...

and promotes their fusion # The entry of the

viral core A capsid is the protein shell of a virus, enclosing its genetic material. It consists of several oligomeric (repeating) structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or ma ...

into the cell Entry inhibitors work by interfering with one aspect of this process.

Approved agents

Maraviroc Maraviroc, sold under the brand names Selzentry (US) and Celsentri (EU), is an antiretroviral medication used to treat HIV infection. It is taken by mouth. It is in the CCR5 receptor antagonist class. It was approved for medical use in the Un ...

binds to

, preventing an interaction with

. It is also referred to as a "chemokine receptor antagonist" or a "CCR5 inhibitor." *

Enfuvirtide Enfuvirtide (International Nonproprietary Name, INN), sold under the brand name Fuzeon, is an HIV fusion inhibitor, the first of a class of antiretroviral drugs used in combination therapy for the treatment of AIDS/HIV. Medical uses Enfuvirti ...

binds to gp41 and interferes with its ability to approximate the two membranes. It is also referred to as a "fusion inhibitor." *

Ibalizumab Ibalizumab, sold under the brand name Trogarzo, is a non-immunosuppressive humanised monoclonal antibody that binds CD4, the primary receptor for HIV, and inhibits HIV from entering cells. It is a post-attachment inhibitor, blocking HIV from bi ...

, a

monoclonal antibody A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodie ...

that binds to domain 2 of CD4 and interferes with post-attachment steps required for the entry of HIV-1 virus particles into host cells and prevents the viral transmission that occurs via cell-cell fusion. *

Fostemsavir Fostemsavir, sold under the brand name Rukobia, is an antiretroviral medication for adults living with HIV/AIDS who have tried multiple HIV medications and whose HIV infection cannot be successfully treated with other therapies because of resist ...

, an attachment inhibitor that interferes with the interaction of CD4 and

by binding with

Investigational 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.

Merck Manual ''The Merck Manual of Diagnosis and Therapy'', referred to as ''The Merck Manual'', is the world's best-selling medical textbook, and the oldest continuously published English language medical textbook. First published in 1899, the current print e ...

.com Human Immunodeficiency Virus (HIV) Infection Table

/ref> *

Leronlimab Leronlimab (codenamed PRO 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 triple negative breast ...

, a monoclonal antibody that binds CCR5 *

Plerixafor Plerixafor, sold under the brand name Mozobil, is an immunostimulant used to mobilize hematopoietic stem cells in cancer patients into the bloodstream. The stem cells are then extracted from the blood and transplanted back to the patient. The ...

was being developed to interfere with interaction between HIV and CXCR4, but showed little useful antiviral activity in recent trials. *

Epigallocatechin gallate Epigallocatechin gallate (EGCG), also known as epigallocatechin-3-gallate, is the ester of epigallocatechin and gallic acid, and is a type of catechin. EGCG – the most abundant catechin in tea – is a polyphenol under basic research for it ...

, a substance found in

green tea Green tea is a type of tea made from the leaves and buds of the '' Camellia sinensis'' that have not undergone the withering and oxidation process that creates oolong teas and black teas. Green tea originated in China in the late 1st millenn ...

, appears to interact with

as do several other

theaflavin Theaflavin (TF) and its derivatives, known collectively as ''theaflavins'', are antioxidant polyphenols in tea, polyphenols that are formed from the condensation of flavan-3-ols in tea leaves during the enzymatic oxidation (sometimes erroneously re ...

s. * Vicriviroc, similar to maraviroc, is currently undergoing clinical trials for FDA approval. * Aplaviroc, an agent similar to maraviroc and vicriroc. Clinical trials were halted in 2005 over concerns about the drug's safety. * b12 is an

antibody An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as pathogenic bacteria, bacteria and viruses, includin ...

against HIV found in some long-term nonprogressors. It has been found to bind to

at the exact region, or

epitope An 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 binds to the epitope is called a paratope. Although e ...

, where

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. * Griffithsin, 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 Repeat The 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. Domains consisting of ankyrin tandem repeats mediate ...

Proteins ( DARPins) potently block viral entry of diverse strains and are being developed and studied as potential microbicide candidates * A polyclonal caprine antibody is in phase II human

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s that targets, among others sites, the GP41 transmembrane glycoprotein. The trials are being conducted by Virionyx, a New Zealand Company. * VIR-576 is a synthesized peptide which binds to gp41, preventing fusion of the virus with a cell membrane. * ITX5061 for

hepatitis C Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection period, people often have mild or no symptoms. Early symptoms can include ...

References

External links

Fusion Inhibitor Resource Center
* {{HIVpharm