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Advances in Genetics 2011Enveloped viruses penetrate their cell targets following the merging of their membrane with that of the cell. This fusion process is catalyzed by one or several viral... (Review)
Review
Enveloped viruses penetrate their cell targets following the merging of their membrane with that of the cell. This fusion process is catalyzed by one or several viral glycoproteins incorporated on the membrane of the virus. These envelope glycoproteins (EnvGP) evolved in order to combine two features. First, they acquired a domain to bind to a specific cellular protein, named "receptor." Second, they developed, with the help of cellular proteins, a function of finely controlled fusion to optimize the replication and preserve the integrity of the cell, specific to the genus of the virus. Following the activation of the EnvGP either by binding to their receptors and/or sometimes the acid pH of the endosomes, many changes of conformation permit ultimately the action of a specific hydrophobic domain, the fusion peptide, which destabilizes the cell membrane and leads to the opening of the lipidic membrane. The comprehension of these mechanisms is essential to develop medicines of the therapeutic class of entry inhibitor like enfuvirtide (Fuzeon) against human immunodeficiency virus (HIV). In this chapter, we will summarize the different envelope glycoprotein structures that viruses develop to achieve membrane fusion and the entry of the virus. We will describe the different entry pathways and cellular proteins that viruses have subverted to allow infection of the cell and the receptors that are used. Finally, we will illustrate more precisely the recent discoveries that have been made within the field of the entry process, with a focus on the use of pseudoparticles. These pseudoparticles are suitable for high-throughput screenings that help in the development of natural or artificial inhibitors as new therapeutics of the class of entry inhibitors.
Topics: Animals; Cell Membrane; Endocytosis; Endosomes; Enfuvirtide; HIV Envelope Protein gp41; HIV Fusion Inhibitors; High-Throughput Screening Assays; Humans; Hydrogen-Ion Concentration; Membrane Fusion; Peptide Fragments; Protein Binding; Protein Refolding; Protein Structure, Tertiary; Receptors, Virus; Viral Envelope Proteins; Viral Fusion Proteins; Virion; Virus Diseases; Viruses
PubMed: 21310296
DOI: 10.1016/B978-0-12-380860-8.00004-5 -
PloS One Mar 2010Enfuvirtide and T-1249 are two HIV-1 fusion inhibitor peptides that bind to gp41 and prevent its fusogenic conformation, inhibiting viral entry into host cells. Previous...
Enfuvirtide and T-1249 are two HIV-1 fusion inhibitor peptides that bind to gp41 and prevent its fusogenic conformation, inhibiting viral entry into host cells. Previous studies established the relative preferences of these peptides for membrane model systems of defined lipid compositions. We aimed to understand the interaction of these peptides with the membranes of erythrocytes and peripheral blood mononuclear cells. The peptide behavior toward cell membranes was followed by di-8-ANEPPS fluorescence, a lipophilic probe sensitive to the changes in membrane dipole potential. We observed a fusion inhibitor concentration-dependent decrease on the membrane dipole potential. Quantitative analysis showed that T-1249 has an approximately eight-fold higher affinity towards cells, when compared with enfuvirtide. We also compared the binding towards di-8-ANEPPS labeled lipid vesicles that model cell membranes and obtained concordant results. We demonstrated the distinct enfuvirtide and T-1249 membranotropism for circulating blood cells, which can be translated to a feasible in vivo scenario. The enhanced interaction of T-1249 with cell membranes correlates with its higher efficacy, as it can increase and accelerate the drug binding to gp41 in its pre-fusion state.
Topics: Cell Membrane; Enfuvirtide; Erythrocyte Membrane; HIV Envelope Protein gp41; HIV Fusion Inhibitors; Humans; Kinetics; Leukocytes, Mononuclear; Lipids; Lymphocytes; Microscopy, Confocal; Peptide Fragments; Peptides; Protein Binding; Protein Structure, Tertiary; Pyridinium Compounds
PubMed: 20352107
DOI: 10.1371/journal.pone.0009830 -
Viruses Aug 2019Application of highly active antiretroviral drugs (ARDs) effectively reduces morbidity and mortality in HIV-infected individuals. However, the emergence of multiple... (Review)
Review
Application of highly active antiretroviral drugs (ARDs) effectively reduces morbidity and mortality in HIV-infected individuals. However, the emergence of multiple drug-resistant strains has led to the increased failure of ARDs, thus calling for the development of anti-HIV drugs with targets or mechanisms of action different from those of the current ARDs. The first peptide-based HIV entry inhibitor, enfuvirtide, was approved by the U.S. FDA in 2003 for treatment of HIV/AIDS patients who have failed to respond to the current ARDs, which has stimulated the development of several series of protein- and peptide-based HIV entry inhibitors in preclinical and clinical studies. In this review, we highlighted the properties and mechanisms of action for those promising protein- and peptide-based HIV entry inhibitors targeting the HIV-1 gp120 or gp41 and discussed their advantages and disadvantages, compared with the current ARDs.
Topics: Antibodies; HIV Envelope Protein gp120; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Peptide Fragments; Recombinant Proteins; Virus Internalization
PubMed: 31374953
DOI: 10.3390/v11080705 -
British Journal of Clinical Pharmacology Dec 2010The strong need for the development of alternative anti-HIV agents is primarily due to the emergence of strain-resistant viruses, the need for sustained adherence to... (Review)
Review
The strong need for the development of alternative anti-HIV agents is primarily due to the emergence of strain-resistant viruses, the need for sustained adherence to complex treatment regimens and the toxicity of currently used antiviral drugs. This review analyzes proof of concept studies indicating that the immunomodulatory drug rapamycin (RAPA) possesses anti-HIV properties both in vitro and in vivo that qualifies it as a potential new anti-HIV drug. It represents a literature review of published studies that evaluated the in vitro and in vivo activity of RAPA in HIV. RAPA represses HIV-1 replication in vitro through different mechanisms including, but not limited, to down regulation of CCR5. In addition RAPA synergistically enhances the anti-HIV activity of entry inhibitors such as vicriviroc, aplaviroc and enfuvirtide in vitro. RAPA also inhibits HIV-1 infection in human peripheral blood leucocytes-SCID reconstituted mice. In addition, a prospective nonrandomized trial of HIV patient series receiving RAPA monotherapy after liver transplantation indicated significantly better control of HIV and hepatitis C virus (HCV) replication among patients taking RAPA monotherapy. Taken together, the evidence presented in this review suggests that RAPA may be a useful drug that should be evaluated for the prevention and treatment of HIV-1 infection.
Topics: Animals; Anti-HIV Agents; Drug Evaluation, Preclinical; Drug Interactions; HIV Infections; HIV-1; Humans; Mice; Sirolimus; Translational Research, Biomedical; Virus Replication
PubMed: 21175433
DOI: 10.1111/j.1365-2125.2010.03735.x -
International Journal of Molecular... Mar 2023Currently, it is estimated that 1-2 million people worldwide are infected with HIV-2, accounting for 3-5% of the global burden of HIV. The course of HIV-2 infection is... (Review)
Review
Currently, it is estimated that 1-2 million people worldwide are infected with HIV-2, accounting for 3-5% of the global burden of HIV. The course of HIV-2 infection is longer compared to HIV-1 infection, but without effective antiretroviral therapy (ART), a substantial proportion of infected patients will progress to AIDS and die. Antiretroviral drugs in clinical use were designed for HIV-1 and, unfortunately, some do not work as well, or do not work at all, for HIV-2. This is the case for non-nucleoside reverse transcriptase inhibitors (NNRTIs), the fusion inhibitor enfuvirtide (T-20), most protease inhibitors (PIs), the attachment inhibitor fostemsavir and most broadly neutralizing antibodies. Integrase inhibitors work well against HIV-2 and are included in first-line therapeutic regimens for HIV-2-infected patients. However, rapid emergence of drug resistance and cross-resistance within each drug class dramatically reduces second-line treatment options. New drugs are needed to treat infection with drug-resistant isolates. Here, we review the therapeutic armamentarium available to treat HIV-2-infected patients, as well as promising drugs in development. We also review HIV-2 drug resistance mutations and resistance pathways that develop in HIV-2-infected patients under treatment.
Topics: Humans; HIV-2; HIV Infections; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Reverse Transcriptase Inhibitors; Drug Resistance, Viral
PubMed: 36982978
DOI: 10.3390/ijms24065905 -
Current Topics in Medicinal Chemistry 2016Human immunodeficiency virus type 1 (HIV-1) envelope (Env) glycoprotein surface subunit gp120 and transmembrane subunit gp41 play important roles in HIV-1 entry, thus... (Review)
Review
Human immunodeficiency virus type 1 (HIV-1) envelope (Env) glycoprotein surface subunit gp120 and transmembrane subunit gp41 play important roles in HIV-1 entry, thus serving as key targets for the development of HIV-1 entry inhibitors. T20 peptide (enfuvirtide) is the first U.S. FDA-approved HIV entry inhibitor; however, its clinical application is limited by the lack of oral availability. Here, we have described the structure and function of the HIV-1 gp120 and gp41 subunits and reviewed advancements in the development of small-molecule HIV entry inhibitors specifically targeting these two Env glycoproteins. We then compared the advantages and disadvantages of different categories of HIV entry inhibitor candidates and further predicted the future trend of HIV entry inhibitor development.
Topics: Anti-HIV Agents; HIV Envelope Protein gp120; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV-1; Humans; Small Molecule Libraries; Virus Internalization
PubMed: 26324044
DOI: 10.2174/1568026615666150901114527 -
Current HIV/AIDS Reports Jun 2017This review focuses on the differential effects of contemporary antiretrovirals on systemic inflammation as heightened immune activation is linked to important... (Review)
Review
PURPOSE OF REVIEW
This review focuses on the differential effects of contemporary antiretrovirals on systemic inflammation as heightened immune activation is linked to important co-morbidities and mortality with HIV infection.
RECENT FINDINGS
Antiretroviral therapy (ART) reduces dramatically systemic inflammation and immune activation, but not to levels synchronous with HIV-uninfected populations. In one ART initiation trial, integrase inhibitors appear to reduce inflammation to a greater degree than non-nucleoside reverse transcriptase inhibitors (NNRTIs); however, it is not clear that there are beneficial effects on inflammation resulting from treatment with integrase inhibitors compared to PIs, between PIs and NNRTIs, between specific nucleoside reverse transcriptase inhibitors, or with maraviroc in ART-naïve patients. In ART switch studies, changing to an integrase inhibitor from a PI-, NNRTI-, or enfuvirtide-containing regimen has resulted in improvement in several markers of inflammation. Additional research is needed to conclusively state whether there are clear differences in effects of specific antiretrovirals on inflammation and immune activation in HIV.
Topics: Anti-HIV Agents; Antiretroviral Therapy, Highly Active; HIV Infections; HIV-1; Humans; Inflammation; Reverse Transcriptase Inhibitors
PubMed: 28434169
DOI: 10.1007/s11904-017-0356-x -
Current Medicinal Chemistry Nov 2001Virtually all the compounds that are currently used, or under advanced clinical trial, for the treatment of HIV infections, belong to one of the following classes: (i)... (Review)
Review
Virtually all the compounds that are currently used, or under advanced clinical trial, for the treatment of HIV infections, belong to one of the following classes: (i) nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs): i.e., zidovudine (AZT), didanosine (ddI), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), abacavir (ABC), emtricitabine [(-)FTC], tenofovir (PMPA) disoproxil fumarate; (ii) non-nucleoside reverse transcriptase inhibitors (NNRTIs): i.e., nevirapine, delavirdine, efavirenz, emivirine (MKC-442); and (iii) protease inhibitors (PIs): i.e., saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, and lopinavir. In addition to the reverse transcriptase and protease step, various other events in the HIV replicative cycle are potential targets for chemotherapeutic intervention: (i) viral adsorption, through binding to the viral envelope glycoprotein gp120 (polysulfates, polysulfonates, polyoxometalates, zintevir, negatively charged albumins, cosalane analogues); (ii) viral entry, through blockade of the viral coreceptors CXCR4 and CCR5 [bicyclams (i.e. AMD3100), polyphemusins (T22), TAK-779, MIP-1 alpha LD78 beta isoform]; (iii) virus-cell fusion, through binding to the viral glycoprotein gp41 [T-20 (DP-178), T-1249 (DP-107), siamycins, betulinic acid derivatives]; (iv) viral assembly and disassembly, through NCp7 zinc finger-targeted agents [2,2'-dithiobisbenzamides (DIBAs), azadicarbonamide (ADA) and NCp7 peptide mimics]; (v) proviral DNA integration, through integrase inhibitors such as L-chicoric acid and diketo acids (i.e. L-731,988); (vi) viral mRNA transcription, through inhibitors of the transcription (transactivation) process (fluoroquinolone K-12, Streptomyces product EM2487, temacrazine, CGP64222). Also, in recent years new NRTIs, NNRTIs and PIs have been developed that possess respectively improved metabolic characteristics (i.e. phosphoramidate and cyclosaligenyl pronucleotides of d4T), or increased activity against NNRTI-resistant HIV strains [second generation NNRTIs, such as capravirine and the novel quinoxaline, quinazolinone, phenylethylthiazolylthiourea (PETT) and emivirine (MKC-442) analogues], or, as in the case of PIs, a different, non-peptidic scaffold [i.e. cyclic urea (DMP 450), 4-hydroxy-2-pyrone (tipranavir)]. Given the multitude of molecular targets with which anti-HIV agents can interact, one should be cautious in extrapolating from cell-free enzymatic assays to the mode of action of these agents in intact cells. A number of compounds (i.e. zintevir and L-chicoric acid, on the one hand; and CGP64222 on the other hand) have recently been found to interact with virus-cell binding and viral entry in contrast to their proposed modes of action targeted at the integrase and transactivation process, respectively.
Topics: Amino Acid Sequence; Animals; Anti-HIV Agents; Binding Sites; Capsid; Capsid Proteins; Drug Design; Enfuvirtide; Enzyme Inhibitors; Gene Products, gag; HIV; HIV Envelope Protein gp41; HIV Integrase; HIV Reverse Transcriptase; Humans; Molecular Sequence Data; Peptide Fragments; Reverse Transcriptase Inhibitors; Transcription, Genetic; Viral Proteins; gag Gene Products, Human Immunodeficiency Virus
PubMed: 11562282
DOI: 10.2174/0929867013371842 -
Antiviral Chemistry & Chemotherapy Sep 2009There are now 26 antiretroviral drugs and 6 fixed-dose combinations, including reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors and fusion (or... (Review)
Review
There are now 26 antiretroviral drugs and 6 fixed-dose combinations, including reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors and fusion (or entry) inhibitors, approved by the US Food and Drug Administration for clinical use. Although they are clinically effective when used in combination, none of the existing drugs are considered ideal because of toxic side effects and the ascendance of inducing drug-resistant mutants. Development of new antiviral agents is essential. In the past decades, there has been great progress in understanding the structure of HIV type-1 (HIV-1) gp41 and the mechanism of HIV-1 entry into host cells. This opened up a promising avenue for rationally designed agents to interfere with this process. A number of fusion inhibitors have been developed to block HIV-1 replication. Enfuvirtide (T20) was one of those approved for clinical use. This signalled a new era in AIDS therapeutics. It is a synthetic polypeptide with potent inhibitory activity against HIV-1 infection. However, it is sensitive to proteolytic digestion and resistant virus strains are easily induced with multiple clinical use. One of the directions in designing new fusion inhibitors is to overcome these shortages. In the past years, large numbers of promising fusion inhibitory peptides have emerged. The antiviral activities are more potent or they can act differently from that of T20. Some of these new compounds have great potential to be further developed as therapeutic agents. This article reviewed some recent developments of these peptides and the possible role in anti-HIV-1 therapy.
Topics: Drug Design; Drug Resistance, Multiple, Viral; HIV Envelope Protein gp41; HIV Fusion Inhibitors; Humans; Peptide Fragments
PubMed: 19794228
DOI: 10.3851/IMP1369 -
Antimicrobial Agents and Chemotherapy Dec 2008Enfuvirtide is the first fusion and entry inhibitor approved for use for the treatment of human immunodeficiency virus (HIV) type 1 infection and as such represents a... (Clinical Trial)
Clinical Trial
Safety and efficacy of enfuvirtide in combination with darunavir-ritonavir and an optimized background regimen in treatment-experienced human immunodeficiency virus-infected patients: the below the level of quantification study.
Enfuvirtide is the first fusion and entry inhibitor approved for use for the treatment of human immunodeficiency virus (HIV) type 1 infection and as such represents a novel class of agents. For the population of patients experienced with three antiretroviral classes, enfuvirtide provides an additional option for treatment. This prospective, open-label, 24-week, single-arm trial assessed the efficacy and safety of enfuvirtide (90 mg injected subcutaneously twice daily) in combination with darunavir-ritonavir (600/100 mg administered orally twice daily) in triple-antiretroviral-class-experienced adults failing their current regimen. The primary efficacy endpoint was the proportion of participants with plasma HIV RNA loads of <50 copies/ml. Other virological and immunological measures were also evaluated, as were the effects of the baseline viral coreceptor tropism and darunavir phenotype sensitivity scores on the outcomes. At week 24, 60.3%, 72.5%, and 84.0% of 131 participants achieved viral loads of <50 copies/ml and <400 copies/ml and a change from the baseline load of > or =1 log(10) copies/ml, respectively. A baseline viral load of < or =5 log(10) copies/ml was a significant predictor of achieving a viral load of <50 copies/ml at 24 weeks; however, neither background genotype sensitivity nor darunavir phenotype sensitivity was a significant predictor of the achievement of viral loads of <50 copies/ml. Although these findings are limited by the relatively small numbers of participants with darunavir susceptibility changes of > or =10-fold, they suggest that combining enfuvirtide and darunavir-ritonavir with an optimized background regimen in triple-class experienced participants naïve to these agents can result in positive virological and immunological responses regardless of most baseline parameters.
Topics: Adult; Anti-HIV Agents; Darunavir; Drug Resistance, Viral; Drug Therapy, Combination; Enfuvirtide; Female; HIV Envelope Protein gp41; HIV Fusion Inhibitors; HIV Infections; HIV Protease Inhibitors; Humans; Male; Middle Aged; Peptide Fragments; Ritonavir; Sulfonamides; Treatment Outcome
PubMed: 18809940
DOI: 10.1128/AAC.00467-08