scholarly journals Conformational flexibility of the conserved hydrophobic pocket of HIV-1 gp41. Implications for the discovery of small-molecule fusion inhibitors

2021 ◽  
Author(s):  
Mario Cano-Muñoz ◽  
Samuel Jurado ◽  
Bertrand Morel ◽  
Francisco Conejero-Lara
Keyword(s):  
Small Molecule ◽  
Conformational Flexibility ◽  
Hydrophobic Pocket ◽  
Fusion Inhibitors ◽  
Hiv 1

scholarly journals N-Substituted Pyrrole Derivatives as Novel Human Immunodeficiency Virus Type 1 Entry Inhibitors That Interfere with the gp41 Six-Helix Bundle Formation and Block Virus Fusion

2004 ◽  
Vol 48 (11) ◽  
pp. 4349-4359 ◽  
Author(s):  
Shibo Jiang ◽  
Hong Lu ◽  
Shuwen Liu ◽  
Qian Zhao ◽  
Yuxian He ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Small Molecule ◽  
Cooh Group ◽  
Hydrophobic Pocket ◽  
Fusion Inhibitors ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT A recently approved peptidic human immunodeficiency virus type 1 (HIV-1) fusion inhibitor, T-20 (Fuzeon; Trimeris Inc.), has shown significant promise in clinical application for treating HIV-1-infected individuals who have failed to respond to the currently available antiretroviral drugs. However, T-20 must be injected twice daily and is too expensive. Therefore, it is essential to develop orally available small molecule HIV-1 fusion inhibitors. By screening a chemical library consisting of “drug-like” compounds, we identified two N-substituted pyrroles, designated NB-2 and NB-64, that inhibited HIV-1 replication at a low micromolar range. The absence of the COOH group in NB-2 and NB-64 resulted in a loss of anti-HIV-1 activity, suggesting that this acid group plays an important role in mediating the antiviral activity. NB-2 and NB-64 inhibited HIV-1 fusion and entry by interfering with the gp41 six-helix bundle formation and disrupting the α-helical conformation. They blocked a d-peptide binding to the hydrophobic pocket on surface of the gp41 internal trimeric coiled-coil domain. Computer-aided molecular docking analysis has shown that they fit inside the hydrophobic pocket and that their COOH group interacts with a positively charged residue (K574) around the pocket to form a salt bridge. These results suggest that NB-2 and NB-64 may bind to the gp41 hydrophobic pocket through hydrophobic and ionic interactions and block the formation of the fusion-active gp41 core, thereby inhibiting HIV-1-mediated membrane fusion and virus entry. Therefore, NB-2 and NB-64 can be used as lead compounds toward designing and developing more potent small molecule HIV-1 fusion inhibitors targeting gp41.

Development of Peptide and Small-Molecule HIV-1 Fusion Inhibitors that Target gp41

ChemMedChem ◽  
2010 ◽  
Vol 5 (11) ◽  
pp. 1813-1824 ◽  
Author(s):  
Lifeng Cai ◽  
Shibo Jiang
Keyword(s):  
Small Molecule ◽  
Fusion Inhibitors ◽  
Hiv 1

scholarly journals Development of Indole Compounds as Small Molecule Fusion Inhibitors Targeting HIV-1 Glycoprotein-41

2011 ◽  
Vol 54 (20) ◽  
pp. 7220-7231 ◽  
Author(s):  
Guangyan Zhou ◽  
Dong Wu ◽  
Beth Snyder ◽  
Roger G. Ptak ◽  
Harmeet Kaur ◽  
...  
Keyword(s):  
Small Molecule ◽  
Fusion Inhibitors ◽  
Indole Compounds ◽  
Hiv 1

scholarly journals Evaluation of ligand-based NMR screening methods to characterize small molecule binding to HIV-1 glycoprotein-41

2017 ◽  
Vol 15 (24) ◽  
pp. 5210-5219 ◽  
Author(s):  
Shidong Chu ◽  
Guangyan Zhou ◽  
Miriam Gochin
Keyword(s):  
Small Molecule ◽  
Binding Mode ◽  
Screening Methods ◽  
Hydrophobic Pocket ◽  
Nmr Screening ◽  
Std Nmr ◽  
Hiv 1

STD NMR pinpoints the binding mode of a small ligand in the hydrophobic pocket of gp41.

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

scholarly journals A small molecule, ACAi-028, with anti-HIV-1 activity targets a novel hydrophobic pocket on HIV-1 capsid

2021 ◽  
Author(s):  
Tomofumi Nakamura ◽  
Travis chia ◽  
Masayuki Amano ◽  
Nobutoki Takamune ◽  
Masao Matsuoka ◽  
...  
Keyword(s):  
Thermal Stability ◽  
Reverse Transcriptase ◽  
Small Molecule ◽  
Early Stage ◽  
Integrase Inhibitor ◽  
Ionization Mass ◽  
Hydrophobic Pocket ◽  
Binding Model ◽  
Anti Hiv ◽  
Hiv 1

The human immunodeficiency virus type 1 (HIV-1) capsid (CA) is an essential viral component of HIV-1 infection, and an attractive therapeutic target for antivirals. We report that a small molecule, ACAi-028, inhibits HIV-1 replication by targeting a hydrophobic pocket in the N-terminal domain of CA (CA-NTD). ACAi-028 is one of more than 40 candidate anti-HIV-1 compounds identified by in silico screening and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Our binding model showed that ACAi-028 interacts with the Q13, S16, and T19 amino acid residues, via hydrogen bonds, in the targeting pocket of CA-NTD. Using recombinant fusion methods, TZM-bl, time-of-addition, and colorimetric reverse transcriptase (RT) assays, the compound was found to exert anti-HIV-1 activity in the early stage between a reverse transcriptase inhibitor, azidothymidine (AZT), and an integrase inhibitor, raltegravir (RAL), without any effect on RT activity, suggesting that this compound may affect HIV-1 core disassembly (uncoating). Moreover, electrospray ionization mass spectrometry (ESI-MS) also showed that the compound binds directly and non-covalently to the CA monomer. CA multimerization and thermal stability assays showed that ACAi-028 decreased CA multimerization and thermal stability via S16 or T19 residues.

scholarly journals A small molecule, ACAi-028, with anti-HIV-1 activity targets a novel hydrophobic pocket on HIV-1 capsid

2021 ◽  
Author(s):  
Travis Chia ◽  
Tomofumi Nakamura ◽  
Masayuki Amano ◽  
Nobutoki Takamune ◽  
Masao Matsuoka ◽  
...  
Keyword(s):  
Thermal Stability ◽  
Small Molecule ◽  
Early Stage ◽  
Ionization Mass ◽  
Hydrophobic Pocket ◽  
Binding Model ◽  
Fusion Methods ◽  
Anti Hiv ◽  
Hiv 1

The human immunodeficiency virus type 1 (HIV-1) capsid (CA) is an essential viral component of HIV-1 infection and an attractive therapeutic target for antivirals. We report that a small molecule, ACAi-028, inhibits HIV-1 replication by targeting a hydrophobic pocket in the N-terminal domain of CA (CA-NTD). ACAi-028 is one of more than 40 candidate anti-HIV-1 compounds identified by in silico screening and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Our binding model showed that ACAi-028 interacts with the Q13, S16, and T19 amino acid residues, via hydrogen bonds, in the targeting pocket of CA-NTD. Using recombinant fusion methods, TZM-bl, time-of-addition, and colorimetric reverse transcriptase (RT) assays, the compound was found to exert anti-HIV-1 activity in the early stage between reverse transcription and proviral DNA integration, without any effect on RT activity in vitro , suggesting that this compound may affect HIV-1 core disassembly (uncoating) as well as a CA inhibitor, PF74. Moreover, electrospray ionization mass spectrometry (ESI-MS) also showed that the compound binds directly and non-covalently to the CA monomer. CA multimerization and thermal stability assays showed that ACAi-028 decreased CA multimerization and thermal stability via S16 or T19 residues. These results indicate that ACAi-028 is a novel CA inhibitor by binding to the novel hydrophobic pocket in CA-NTD. This study demonstrates that a compound, ACAi-028, targeting the new hydrophobic pocket should be a promising anti-HIV-1 inhibitor.

Development of Small Molecule HIV-1 Fusion Inhibitors: Linking Biology to Chemistry

2013 ◽  
Vol 19 (10) ◽  
pp. 1827-1834 ◽  
Author(s):  
Fusako Miyamoto ◽  
Eiichi N. Kodama
Keyword(s):  
Small Molecule ◽  
Fusion Inhibitors ◽  
Hiv 1

scholarly journals Stable Extended Human Immunodeficiency Virus Type 1 gp41 Coiled Coil as an Effective Target in an Assay for High-Affinity Fusion Inhibitors

2009 ◽  
Vol 53 (6) ◽  
pp. 2444-2449 ◽  
Author(s):  
Lifeng Cai ◽  
Edina Balogh ◽  
Miriam Gochin
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Metal Ion ◽  
Coiled Coil ◽  
Hydrophobic Pocket ◽  
High Affinity ◽  
Fusion Inhibitors ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The human immunodeficiency virus type 1 (HIV-1) gp41 coiled-coil domain is an important target for fusion inhibitors, including the peptide T20, which has been approved as a drug against HIV-1. Research into nonpeptide fusion inhibitors has focused primarily on a hydrophobic pocket located within the coiled coil and has so far yielded compounds with relatively weak fusion inhibitory activity. Here, we describe metal ion-assisted stabilization of an extended 39-residue construct of gp41, which includes residues of the hydrophobic pocket and also of an extended groove N terminal to the hydrophobic pocket. We show that the presence of a metal ion and the high-affinity interaction between the receptor construct and cognate C-peptides result in a simple and highly selective assay for fusion inhibitors that may be used to scan large compound libraries. The long construct presents multiple potential binding sites along the extended coiled-coil groove. We demonstrate the modular use of assay probes to detect whether compounds bind in the hydrophobic pocket or elsewhere along the groove. Rapid detection and quantitation of hits can lead to the discovery of compounds binding to different sites along the groove and provide structure-activity relationship data for optimization. Compounds binding to adjacent sites could be linked to form more potent fusion inhibitors.

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