Investigation into the mechanism of a novel HIV-1 fusion inhibitor, SC12

2021 ◽  
Author(s):  
Marina Tuyishime
Keyword(s):  
Fusion Inhibitor ◽  
Hiv 1

scholarly journals HIV-1 tropism for the central nervous system: Brain-derived envelope glycoproteins with lower CD4 dependence and reduced sensitivity to a fusion inhibitor

Virology ◽  
2006 ◽  
Vol 346 (1) ◽  
pp. 169-179 ◽  
Author(s):  
Julio Martín-García ◽  
Wei Cao ◽  
Angel Varela-Rohena ◽  
Matthew L. Plassmeyer ◽  
Francisco González-Scarano
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Envelope Glycoproteins ◽  
Fusion Inhibitor ◽  
The Central Nervous System ◽  
Hiv 1

scholarly journals Unraveling the Molecular Basis of the Selectivity of the HIV-1 Fusion Inhibitor Sifuvirtide Towards Phosphatidylcholine-Rich Rigid Membranes

2010 ◽  
Vol 98 (3) ◽  
pp. 279a
Author(s):  
Henri G. Franquelim ◽  
A. Salomé Veiga ◽  
Nuno C. Santos ◽  
Miguel A.R.B. Castanho
Keyword(s):  
Molecular Basis ◽  
Fusion Inhibitor ◽  
Hiv 1

scholarly journals Molecular mechanism of HIV-1 resistance to sifuvirtide, a clinical trial–approved membrane fusion inhibitor

2018 ◽  
Vol 293 (33) ◽  
pp. 12703-12718 ◽  
Author(s):  
Danwei Yu ◽  
Xiaohui Ding ◽  
Zixuan Liu ◽  
Xiyuan Wu ◽  
Yuanmei Zhu ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Membrane Fusion ◽  
Molecular Mechanism ◽  
Fusion Inhibitor ◽  
Hiv 1

scholarly journals Therapeutic Efficacy and Resistance Selection of a Lipopeptide Fusion Inhibitor in Simian Immunodeficiency Virus-Infected Rhesus Macaques

2020 ◽  
Vol 94 (15) ◽  
Author(s):  
Danwei Yu ◽  
Jing Xue ◽  
Huamian Wei ◽  
Zhe Cong ◽  
Ting Chen ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Therapeutic Efficacy ◽  
Rhesus Macaques ◽  
Heptad Repeat ◽  
Fusion Inhibitor ◽  
Resistance Mutations ◽  
Fusion Inhibitors ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT We recently reported a group of lipopeptide-based membrane fusion inhibitors with potent antiviral activities against human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus (SIV). In this study, the in vivo therapeutic efficacy of such a lipopeptide, LP-52, was evaluated in rhesus macaques chronically infected with pathogenic SIVmac239. In a pilot study with one monkey, monotherapy with low-dose LP-52 rapidly reduced the plasma viral loads to below the limit of detection and maintained viral suppression during three rounds of structurally interrupted treatment. The therapeutic efficacy of LP-52 was further verified in four infected monkeys; however, three out of the monkeys had viral rebounds under the LP-52 therapy. We next focused on characterizing SIV mutants responsible for the in vivo resistance. Sequence analyses revealed that a V562A or V562M mutation in the N-terminal heptad repeat (NHR) and a E657G mutation in the C-terminal heptad repeat (CHR) of SIV gp41 conferred high resistance to LP-52 and cross-resistance to the peptide drug T20 and two newly designed lipopeptides (LP-80 and LP-83). Moreover, we showed that the resistance mutations greatly reduced the stability of diverse fusion inhibitors with the NHR site, and V562A or V562M in combination with E657G could significantly impair the functionality of viral envelopes (Envs) to mediate SIVmac239 infection and decrease the thermostability of viral six-helical bundle (6-HB) core structure. In conclusion, the present data have not only facilitated the development of novel anti-HIV drugs that target the membrane fusion step, but also help our understanding of the mechanism of viral evolution to develop drug resistance. IMPORTANCE The anti-HIV peptide drug T20 (enfuvirtide) is the only membrane fusion inhibitor available for treatment of viral infection; however, it exhibits relatively weak antiviral activity, short half-life, and a low genetic barrier to inducing drug resistance. Design of lipopeptide-based fusion inhibitors with extremely potent and broad antiviral activities against divergent HIV-1, HIV-2, and SIV isolates have provided drug candidates for clinical development. Here, we have verified a high therapeutic efficacy for the lipopeptide LP-52 in SIVmac239-infected rhesus monkeys. The resistance mutations selected in vivo have also been characterized, providing insights into the mechanism of action of newly designed fusion inhibitors with a membrane-anchoring property. For the first time, the data show that HIV-1 and SIV can share a similar genetic pathway to develop resistance, and that a lipopeptide fusion inhibitor could have a same resistance profile as its template peptide.

scholarly journals Mechanism of HIV-1 Resistance to an Electronically Constrained α-Helical Peptide Membrane Fusion Inhibitor

2018 ◽  
Vol 92 (7) ◽  
Author(s):  
Xiyuan Wu ◽  
Zixuan Liu ◽  
Xiaohui Ding ◽  
Danwei Yu ◽  
Huamian Wei ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Cross Resistance ◽  
Fusion Inhibitor ◽  
Viral Fusion ◽  
Wild Type ◽  
Genetic Pathway ◽  
Fusion Inhibitors ◽  
Helical Peptide ◽  
Mimic Peptide ◽  
Hiv 1

ABSTRACTSC29EK is an electronically constrained α-helical peptide HIV-1 fusion inhibitor that is highly effective against both wild-type and enfuvirtide (T20)-resistant viruses. In this study, we focused on investigating the mechanism of HIV-1 resistance to SC29EK by two approaches. First, SC29EK-escaping HIV-1 variants were selected and characterized. Three mutant viruses, which possessed two (N43K/E49A) or three (Q39R/N43K/N126K and N43K/E49A/N126K) amino acid substitutions in the N- and C-terminal repeat regions of gp41 were identified as conferring high resistance to SC29EK and cross-resistance to the first-generation (T20 and C34) and newly designed (sifuvirtide, MT-SC29EK, and 2P23) fusion inhibitors. The resistance mutations could reduce the binding stability of SC29EK, impair viral Env-mediated cell fusion and entry, and change the conformation of the gp41 core structure. Further, we determined the crystal structure of SC29EK in complex with a target mimic peptide, which revealed the critical intra- and interhelical interactions underlying the mode of action of SC29EK and the genetic pathway to HIV-1 resistance. Taken together, the present data provide new insights into the structure and function of gp41 and the structure-activity relationship (SAR) of viral fusion inhibitors.IMPORTANCET20 is the only membrane fusion inhibitor available for treatment of viral infection, but it has relatively low anti-HIV activity and genetic barriers for resistance, thus calling for new drugs blocking the viral fusion process. As an electronically constrained α-helical peptide, SC29EK is highly potent against both wild-type and T20-resistant HIV-1 strains. Here, we report the characterization of HIV-1 variants resistant to SC29EK and the crystal structure of SC29EK. The key mutations mediating high resistance to SC29EK and cross-resistance to the first and new generations of fusion inhibitors as well as the underlying mechanisms were identified. The crystal structure of SC29EK bound to a target mimic peptide further revealed its action mode and genetic pathway to inducing resistance. Hence, our data have shed new lights on the mechanisms of HIV-1 fusion and its inhibition.

scholarly journals Impact of Human Immunodeficiency Virus Type 1 gp41 Amino Acid Substitutions Selected during Enfuvirtide Treatment on gp41 Binding and Antiviral Potency of Enfuvirtide In Vitro

2005 ◽  
Vol 79 (19) ◽  
pp. 12447-12454 ◽  
Author(s):  
M. Mink ◽  
S. M. Mosier ◽  
S. Janumpalli ◽  
D. Davison ◽  
L. Jin ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Amino Acid ◽  
Binding Affinity ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Fusion Inhibitor ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Enfuvirtide (ENF), a novel human immunodeficiency virus type 1 (HIV-1) fusion inhibitor, has potent antiviral activity against HIV-1 both in vitro and in vivo. Resistance to ENF observed after in vitro passaging was associated with changes in a three-amino-acid (aa) motif, GIV, at positions 36 to 38 of gp41. Patients with ongoing viral replication while receiving ENF during clinical trials acquired substitutions within gp41 aa 36 to 45 in the first heptad repeat (HR-1) of gp41 in both population-based plasma virus sequences and proviral DNA sequences from isolates showing reduced susceptibilities to ENF. To investigate their impact on ENF susceptibility, substitutions were introduced into a modified pNL4-3 strain by site-directed mutagenesis, and the susceptibilities of mutant viruses and patient-derived isolates to ENF were tested. In general, susceptibility decreases for single substitutions were lower than those for double substitutions, and the levels of ENF resistance seen for clinical isolates were higher than those observed for the site-directed mutant viruses. The mechanism of ENF resistance was explored for a subset of the substitutions by expressing them in the context of a maltose binding protein chimera containing a portion of the gp41 ectodomain and measuring their binding affinity to fluorescein-labeled ENF. Changes in binding affinity for the mutant gp41 fusion proteins correlated with the ENF susceptibilities of viruses containing the same substitutions. The combined results support the key role of gp41 aa 36 to 45 in the development of resistance to ENF and illustrate that additional envelope regions contribute to the ENF susceptibility of fusion inhibitor-naïve viruses and resistance to ENF.

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