A novel neutralization epitope on the 'thumb' subdomain of human immunodeficiency virus type 1 reverse transcriptase revealed by a monoclonal antibody

Chiba, Joe; Yamaguchi, A.; Nakano, Masakazu; Zhu, Wei; Ohba, Hiroyoshi; Saito, Atsushi; Shinagawa, Hideo; Yamakawa, Yoshio; Kobayashi, Toshiaki; Kurata, Takeshi

doi:10.1099/0022-1317-77-12-2921

Cited by 11 publications

(16 citation statements)

References 39 publications

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“…B, SDS-polyacrylamide gel electrophoresis of purified RTs. C, Western blot analysis using the mouse monoclonal antibody 7C4, which recognizes a sequential epitope present in HIV-1 group M:subtype B RTs (34) Expression and Purification of HIV-1 RT-Purification of HIV-1 RT variants was carried out after independent expression of each subunit, i.e. p66 and p51 (26).…”

Section: /Ebi Data Bank With Accession Number(s) Af068947 and Af378083mentioning

confidence: 99%

Functional Characterization of Chimeric Reverse Transcriptases with Polypeptide Subunits of Highly Divergent HIV-1 Group M and O Strains

Menéndez‐Arias¹,

Abraha²,

Quiñones‐Mateu³

et al. 2001

Journal of Biological Chemistry

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Section: /Ebi Data Bank With Accession Number(s) Af068947 and Af378083mentioning

confidence: 99%

Functional Characterization of Chimeric Reverse Transcriptases with Polypeptide Subunits of Highly Divergent HIV-1 Group M and O Strains

Menéndez‐Arias¹,

Abraha²,

Quiñones‐Mateu³

et al. 2001

Journal of Biological Chemistry

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“…1). Rather than chelating divalent metal in the RNase H active site, which is the proposed mechanism for many RNase H inhibitors (12,16), compound 1 was postulated to interact with the p51 thumb subdomain, possibly affecting the conformation of the immediately adjacent p66 RNase H domain (2,9,11,14). Unlike ␤-thujaplicinol, which can be displaced from the RNase H active site by nucleic acid, the data presented in this communication illustrate that vinylogous ureas have the advantage that they are still effective in the presence of substrate (3,35).…”

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confidence: 99%

Structure-Activity Analysis of Vinylogous Urea Inhibitors of Human Immunodeficiency Virus-Encoded Ribonuclease H

Chung

Wendeler

Rausch

et al. 2010

Antimicrob Agents Chemother

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Vinylogous ureas 2-amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide and N-[3-(aminocarbonyl)-4,5-dimethyl-2-thienyl]-2-furancarboxamide (compounds 1 and 2, respectively) were recently identified to be modestly potent inhibitors of the RNase H activity of HIV-1 and HIV-2 reverse transcriptase (RT). Both compounds shared a 3-CONH 2 -substituted thiophene ring but were otherwise structurally unrelated, which prevented a precise definition of the pharmacophore. We have therefore examined a larger series of vinylogous ureas carrying amide, amine, and cycloalkane modifications of the thiophene ring of compound 1. While cycloheptane-and cyclohexane-substituted derivatives retained potency, cyclopentane and cyclooctane substitutions eliminated activity. In the presence of a cycloheptane ring, modifying the 2-NH 2 or 3-CONH 2 functions decreased the potency. With respect to compound 2, vinylogous ureas whose dimethylthiophene ring contained modifications of the 2-NH 2 and 3-CONH 2 functions were investigated. 2-NH 2 -modified analogs displayed potency equivalent to or enhanced over that of compound 2, the most active of which, compound 16, reflected intramolecular cyclization of the 2-NH 2 and 3-CONH 2 groups. Molecular modeling was used to define an inhibitor binding site in the p51 thumb subdomain, suggesting that an interaction with the catalytically conserved His539 of the p66 RNase H domain could underlie inhibition of RNase H activity. Collectively, our data indicate that multiple functional groups of vinylogous ureas contribute to their potencies as RNase H inhibitors. Finally, single-molecule spectroscopy indicates that vinylogous ureas have the property of altering the reverse transcriptase orientation on a model RNA-DNA hybrid mimicking initiation plus-strand DNA synthesis.Current success in treating HIV infection and AIDS can be attributed to effective combination antiretroviral therapy involving a cocktail of inhibitors directed primarily against the retroviral protease and reverse transcriptase (RT) (22). Inhibition of RT function is achieved either directly, by incorporating chain-terminating nucleoside derivatives (nucleoside RT inhibitors [NRTIs]), or indirectly, by nonnucleoside RT inhibitors (NNRTIs) that occupy a hydrophobic pocket at the base of the p66 thumb to interrupt the chemical step of DNA synthesis (25)

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“…Biopanning against recombinant RT led to the identification of two Fab fragments (5F and 5G) able to strongly inhibit the RDDP activity of HIV-1 RT. Epitope mapping and competitive ELISA showed that 5F and 5G recognized an epitope similar or closely related to the epitope targeted by the mouse MAb (7C4) previously described by the same authors [119]. …”

Section: Identification Of Hiv-1 Inhibitors By Phage Displaymentioning

confidence: 58%

Phages and HIV-1: From Display to Interplay

Delhalle

Schmit

Chevigné

2012

IJMS

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The complex hide-and-seek game between HIV-1 and the host immune system has impaired the development of an efficient vaccine. In addition, the high variability of the virus impedes the long-term control of viral replication by small antiviral drugs. For more than 20 years, phage display technology has been intensively used in the field of HIV-1 to explore the epitope landscape recognized by monoclonal and polyclonal HIV-1-specific antibodies, thereby providing precious data about immunodominant and neutralizing epitopes. In parallel, biopanning experiments with various combinatorial or antibody fragment libraries were conducted on viral targets as well as host receptors to identify HIV-1 inhibitors. Besides these applications, phage display technology has been applied to characterize the enzymatic specificity of the HIV-1 protease. Phage particles also represent valuable alternative carriers displaying various HIV-1 antigens to the immune system and eliciting antiviral responses. This review presents and summarizes the different studies conducted with regard to the nature of phage libraries, target display mode and biopanning procedures.

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A novel neutralization epitope on the 'thumb' subdomain of human immunodeficiency virus type 1 reverse transcriptase revealed by a monoclonal antibody

Cited by 11 publications

References 39 publications

Functional Characterization of Chimeric Reverse Transcriptases with Polypeptide Subunits of Highly Divergent HIV-1 Group M and O Strains

Functional Characterization of Chimeric Reverse Transcriptases with Polypeptide Subunits of Highly Divergent HIV-1 Group M and O Strains

Structure-Activity Analysis of Vinylogous Urea Inhibitors of Human Immunodeficiency Virus-Encoded Ribonuclease H

Phages and HIV-1: From Display to Interplay

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