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New insights into the interaction between pyrrolyl diketoacids and HIV-1 integrase active site and comparison with RNase H.
- Source :
-
Antiviral research [Antiviral Res] 2016 Oct; Vol. 134, pp. 236-243. Date of Electronic Publication: 2016 Sep 20. - Publication Year :
- 2016
-
Abstract
- HIV-1 integrase (IN) inhibitors are one of the most recent innovations in the treatment of HIV infection. The selection of drug resistance viral strains is however a still open issue requiring constant efforts to identify new anti-HIV-1 drugs. Pyrrolyl diketo acid (DKA) derivatives inhibit HIV-1 replication by interacting with the Mg <superscript>2+</superscript> cofactors within the HIV-1 IN active site or within the HIV-1 reverse-transcriptase associated ribonuclease H (RNase H) active site. While the interaction mode of pyrrolyl DKAs with the RNase H active site has been recently reported and substantiated by mutagenesis experiments, their interaction within the IN active site still lacks a detailed understanding. In this study, we investigated the binding mode of four pyrrolyl DKAs to the HIV-1 IN active site by molecular modeling coupled with site-directed mutagenesis studies showing that the DKA pyrrolyl scaffold primarily interacts with the IN amino residues P145, Q146 and Q148. Importantly, the tested DKAs demonstrated good effectiveness against HIV-1 Raltegravir resistant Y143A and N155H INs, thus showing an interaction pattern with relevant differences if compared with the first generation IN inhibitors. These data provide precious insights for the design of new HIV inhibitors active on clinically selected Raltegravir resistant variants. Furthermore, this study provides new structural information to modulate IN and RNase H inhibitory activities for development of dual-acting anti-HIV agents.<br /> (Copyright © 2016 Elsevier B.V. All rights reserved.)
- Subjects :
- Anti-HIV Agents chemistry
Anti-HIV Agents pharmacology
Binding Sites
Catalytic Domain
Drug Resistance, Viral
HIV Infections virology
HIV Integrase drug effects
HIV Integrase genetics
HIV Integrase Inhibitors chemistry
HIV Integrase Inhibitors pharmacology
HIV-1 drug effects
HIV-1 enzymology
Humans
Models, Molecular
Molecular Structure
Mutagenesis, Site-Directed
Pyrroles chemistry
Pyrroles pharmacology
Ribonuclease H pharmacology
Structure-Activity Relationship
Virus Replication drug effects
HIV Integrase metabolism
HIV Integrase Inhibitors metabolism
HIV-1 metabolism
Pyrroles metabolism
Ribonuclease H metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1872-9096
- Volume :
- 134
- Database :
- MEDLINE
- Journal :
- Antiviral research
- Publication Type :
- Academic Journal
- Accession number :
- 27659398
- Full Text :
- https://doi.org/10.1016/j.antiviral.2016.09.008