COMPUTATIONAL STUDY OF HIV-1 gp41 NHR TRIMER: INHIBITION MECHANISMS OF N-SUBSTITUTED PYRROLE DERIVATIVES AND FRAGMENT-BASED VIRTUAL SCREENING

2013 ◽  
Vol 12 (08) ◽  
pp. 1341001 ◽  
Author(s):  
JU BAO ◽  
JIN F. LIU ◽  
XIAO HE ◽  
JOHN Z. H. ZHANG
Keyword(s):  
Virtual Screening ◽  
Membrane Fusion ◽  
Computational Study ◽  
Antiviral Drug ◽  
Pyrrole Derivatives ◽  
Surface Receptors ◽  
Chemical Structures ◽  
Fusion Inhibitors ◽  
Inhibitory Mechanisms ◽  
Hiv 1

Fusion of HIV-1 viral and host cellular membranes is an important step for HIV infection. The HIV-1 envelope glycoprotein mediating the membrane fusion consists of subunits gp120 and gp41 whereas gp120 recognizes the cell-surface receptors and gp41 promotes viral-cell membrane fusion. The trimeric helical complex composed of heterodimer of N-terminal and C-terminal extraviral segments has been used for the gp41 function study, and the trimeric N-terminal teptad repeat (NHR) is considered as an antiviral drug target for developing HIV-1 membrane fusion inhibitors. By using computational solvent probe mapping, we have explored druggable sites on the trimeric NHR peptides, and identified residues K574 and R579 as the hot spots for inhibitor designing. We further demonstrated that although NB-2 and NB-64 are all N-substituted Pyrrole derivatives and have very similar chemical structures, it is possible that diverse inhibitory mechanisms targeting different negative electrostatic residues (K574 and R579) exist. Results from fragment-based virtual screening identified series of potential lead compounds which could be used for further design of fusion inhibitors.

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 Affinity selection and sequence-activity relationships of HIV-1 membrane fusion inhibitors directed at the drug-resistant variants

MedChemComm ◽  
2010 ◽  
Vol 1 (4) ◽  
pp. 276 ◽  
Author(s):  
Shinya Oishi ◽  
Kentaro Watanabe ◽  
Saori Ito ◽  
Michinori Tanaka ◽  
Hiroki Nishikawa ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Drug Resistant ◽  
Affinity Selection ◽  
Fusion Inhibitors ◽  
Hiv 1

Identification of Novel Potential Inhibitors of the HIV-1 gp41 Protein by Virtual Screening and Molecular Modeling Methods

2015 ◽  
Vol 10 (2) ◽  
pp. 325-343 ◽  
Author(s):  
И.А. Кашин ◽  
I.A. Kashyn
Keyword(s):  
Virtual Screening ◽  
Chemical Compounds ◽  
External Region ◽  
Modeling Methods ◽  
Fusion Inhibitors ◽  
Neutralizing Monoclonal Antibody ◽  
Dynamics Simulations ◽  
Potential Inhibitors ◽  
Free Energy Of Binding ◽  
Hiv 1

Virtual screening of chemical compounds able to mimic pharmacophoric properties of broadly neutralizing monoclonal antibody 10E8 against HIV-1 was carried out. Evaluation of the efficacy of binding of these compounds to the membrane-proximal external region (MPER) of the HIV-1 gp41 protein critical for fusion of the virus membrane with a target cell was performed by molecular docking and molecular dynamics simulations. Eight chemical compounds exhibiting negative values of the free energy of binding to this functionally important site of HIV-1 were identified. The data obtained testify to the availability of these molecules in the studies aimed at the design of novel antiviral drugs presenting the HIV-1 fusion inhibitors that block the MPER region of the gp41 protein.

Recent Advances in the Development of Small-Molecule Compounds Targeting HIV- 1 gp41 as Membrane Fusion Inhibitors

2012 ◽  
Vol 9 (1) ◽  
pp. 20-26
Author(s):  
Norihito Kawashita ◽  
Yu-Shi Tian ◽  
U. Chandimal de Silva ◽  
Kousuke Okamoto ◽  
Tatsuya Takagi
Keyword(s):  
Membrane Fusion ◽  
Small Molecule ◽  
Fusion Inhibitors ◽  
Recent Advances ◽  
Hiv 1

A Computational Approach to Search Active Peptides as Membrane Fusion Inhibitors of HIV-1

2011 ◽  
Vol 90 (2) ◽  
pp. A76-A77
Author(s):  
Yu-Shi Tian ◽  
Norihito Kawashita ◽  
Chris Verathamjamras ◽  
Kousuke Okamoto ◽  
Teruo Yasunaga ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Computational Approach ◽  
Active Peptides ◽  
Fusion Inhibitors ◽  
Hiv 1

Computational Study of Binding Mode for N-substituted Pyrrole Derivatives to HIV-1 gp41*

2010 ◽  
Vol 37 (8) ◽  
pp. 904-915 ◽  
Author(s):  
Xiao-Jing CONG ◽  
Jian-Jun TAN ◽  
Ming LIU ◽  
Wei-Zu CHEN ◽  
Cun-Xin WANG
Keyword(s):  
Computational Study ◽  
Binding Mode ◽  
Pyrrole Derivatives ◽  
Hiv 1

scholarly journals HIV-1 anchor inhibitors and membrane fusion inhibitors target distinct but overlapping steps in virus entry

2019 ◽  
Vol 294 (15) ◽  
pp. 5736-5746 ◽  
Author(s):  
Dirk Eggink ◽  
Ilja Bontjer ◽  
Steven W. de Taeye ◽  
Johannes P. M. Langedijk ◽  
Ben Berkhout ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Virus Entry ◽  
Fusion Inhibitors ◽  
Hiv 1

scholarly journals HIV-1 Entry and Membrane Fusion Inhibitors

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 735
Author(s):  
Tianshu Xiao ◽  
Yongfei Cai ◽  
Bing Chen
Keyword(s):  
Membrane Fusion ◽  
Conformational Changes ◽  
Viral Entry ◽  
Rational Design ◽  
Host Cells ◽  
Structural Basis ◽  
Fusion Inhibitors ◽  
Immunodeficiency Virus ◽  
Chemokine Receptor Ccr5 ◽  
Hiv 1

HIV-1 (human immunodeficiency virus type 1) infection begins with the attachment of the virion to a host cell by its envelope glycoprotein (Env), which subsequently induces fusion of viral and cell membranes to allow viral entry. Upon binding to primary receptor CD4 and coreceptor (e.g., chemokine receptor CCR5 or CXCR4), Env undergoes large conformational changes and unleashes its fusogenic potential to drive the membrane fusion. The structural biology of HIV-1 Env and its complexes with the cellular receptors not only has advanced our knowledge of the molecular mechanism of how HIV-1 enters the host cells but also provided a structural basis for the rational design of fusion inhibitors as potential antiviral therapeutics. In this review, we summarize our latest understanding of the HIV-1 membrane fusion process and discuss related therapeutic strategies to block viral entry.

Binding ofN-substituted pyrrole derivatives to HIV-1 gp41

2014 ◽  
Vol 13 (02) ◽  
pp. 1450018 ◽  
Author(s):  
Kunzhong Song ◽  
Ju Bao ◽  
Yueming Sun ◽  
John Z. H. Zhang
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Computational Study ◽  
Binding Modes ◽  
Binding Mechanism ◽  
Free Energies ◽  
Theoretical Understanding ◽  
Pyrrole Derivatives ◽  
Immunodeficiency Virus ◽  
Hiv 1

Developing small molecule inhibitors of human immunodeficiency virus type 1 (HIV-1) fusion has attracted significant interest. Recently, Jiang have reported several natural and synthetic N -substituted pyrrole derivatives targeting gp41 that are experimentally shown to inhibit cell–cell fusion in the low micromolar range. In order to help gain insight on the binding mechanism, we carried out computational study to help identify possible binding modes and to characterize structures of binding complexes. Detailed gp41-molecule binding interactions and free energies of binding are obtained through molecular dynamics (MD) simulation and MM-PBSA calculation. Specific molecular interactions in the gp41-inhibitor complexes are identified. Current computational study complements the corresponding experimental investigation and provides theoretical understanding on the binding mechanism which is helpful for further refinement of small molecule inhibitors of gp41.

scholarly journals Structural and Functional Characterization of Membrane Fusion Inhibitors with Extremely Potent Activity against Human Immunodeficiency Virus Type 1 (HIV-1), HIV-2, and Simian Immunodeficiency Virus

2018 ◽  
Vol 92 (20) ◽  
Author(s):  
Huihui Chong ◽  
Yuanmei Zhu ◽  
Danwei Yu ◽  
Yuxian He
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Membrane Fusion ◽  
Simian Immunodeficiency Virus ◽  
Genetic Barrier ◽  
Fusion Inhibitors ◽  
Structure Activity ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACTT-20 (enfuvirtide) is the only membrane fusion inhibitor available for the treatment of viral infection; however, it has low anti-human immunodeficiency virus (anti-HIV) activity and a low genetic barrier for drug resistance. We recently reported that T-20 sequence-based lipopeptides possess extremely potentin vitroandin vivoefficacies (X. Ding, Z. Zhang, H. Chong, Y. Zhu, H. Wei, X. Wu, J. He, X. Wang, Y. He, 2017, J Virol 91:e00831-17, https://doi.org/10.1128/JVI.00831-17; H. Chong, J. Xue, Y. Zhu, Z. Cong, T. Chen, Y. Guo, Q. Wei, Y. Zhou, C. Qin, Y. He, 2018, J Virol 92:e00775-18, https://doi.org/10.1128/JVI.00775-18). Here, we focused on characterizing the structure-activity relationships of the T-20 derivatives. First, a novel lipopeptide termed LP-52 was generated with improved target-binding stability and anti-HIV activity. Second, a large panel of truncated lipopeptides was characterized, revealing a 21-amino-acid sequence core structure. Third, it was surprisingly found that the addition of the gp41 pocket-binding residues in the N terminus of the new inhibitors resulted in increased binding but decreased antiviral activities. Fourth, while LP-52 showed the most potent activity in inhibiting divergent HIV-1 subtypes, its truncated versions, such as LP-55 (25-mer) and LP-65 (24-mer), still maintained their potencies at very low picomolar concentrations; however, both the N- and C-terminal motifs of LP-52 played crucial roles in the inhibition of T-20-resistant HIV-1 mutants, HIV-2, and simian immunodeficiency virus (SIV) isolates. Fifth, we verified that LP-52 can bind to target cell membranes and human serum albumin and has low cytotoxicity and a high genetic barrier to inducing drug resistance.IMPORTANCEDevelopment of novel membrane fusion inhibitors against HIV and other enveloped viruses is highly important in terms of the peptide drug T-20, which remains the only one for clinical use, even if it is limited by large dosages and resistance. Here, we report a novel T-20 sequence-based lipopeptide showing extremely potent and broad activities against HIV-1, HIV-2, SIV, and T-20-resistant mutants, as well as an extremely high therapeutic selectivity index and genetic resistance barrier. The structure-activity relationship (SAR) of the T-20 derivatives has been comprehensively characterized, revealing a critical sequence core structure and the target sites of viral vulnerability that do not include the gp41 pocket. The results also suggest that membrane-anchored inhibitors possess unique modes of action relative to unconjugated peptides. Combined, our series studies have not only provided drug candidates for clinical development but also offered important tools to elucidate the mechanisms of viral fusion and inhibition.

Sign in / Sign up

Export Citation Format

Share Document