Quinolinonyl Derivatives as Dual Inhibitors of the HIV-1 Integrase Catalytic Site and Integrase–RNA interactions

The HIV-1 integrase (IN) plays a critical role in the viral lifecycle by integrating the viral DNA into the host chromosome. The catalytic function of IN has been exploited as a target, with five drugs acting as active site binders (IN strand transfer inhibitors, INSTIs). However, IN mutations conferring low-level resistance to INSTIs have been reported. Therefore, new IN inhibitors with different mechanisms of action are needed. The allosteric inhibition of IN, exerted by allosteric IN inhibitors (ALLINIs), is gaining interest. ALLINIs inhibit IN by inducing aberrant IN multimerization with different mechanisms. Furthermore, recent discoveries unveiled that IN has an under-studied yet equally vital second function. This involves IN binding to the RNA genome in virions, necessary for proper virion maturation. In this work, we describe a series of quinolinonyl derivatives as inhibitors of both the IN catalytic functions and IN-RNA interactions, which impair both early and late steps of viral replication.

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Publication Details

Journal
ACS Medicinal Chemistry Letters
Published
2024-08-05
DOI
https://doi.org/10.1021/acsmedchemlett.4c00268
Primary Topic
HIV/AIDS drug development and treatment
Type
article
Field-Weighted Citation Impact
0.00

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article

Quinolinonyl Derivatives as Dual Inhibitors of the HIV-1 Integrase Catalytic Site and Integrase–RNA interactions

Giuseppe Ruggieri, Antonella Messore, Pratibha C. Koneru, Davide Ialongo et al.
ACS Medicinal Chemistry Letters
HIV/AIDS drug development and treatment
article

Quinolinonyl Derivatives as Dual Inhibitors of the HIV-1 Integrase Catalytic Site and Integrase–RNA interactions

Giuseppe Ruggieri, Antonella Messore, Pratibha C. Koneru, Davide Ialongo, Luigi Scipione, Valentina Noemi Madia, Roberta Costi, Roberto Di Santo, Elisa Patacchini, Francesco Saccoliti, Reed Haney, Sandro Cosconati, Mamuka Kvaratskhelia, Aurora Albano
article en

Abstract

The HIV-1 integrase (IN) plays a critical role in the viral lifecycle by integrating the viral DNA into the host chromosome. The catalytic function of IN has been exploited as a target, with five drugs acting as active site binders (IN strand transfer inhibitors, INSTIs). However, IN mutations conferring low-level resistance to INSTIs have been reported. Therefore, new IN inhibitors with different mechanisms of action are needed. The allosteric inhibition of IN, exerted by allosteric IN inhibitors (ALLINIs), is gaining interest. ALLINIs inhibit IN by inducing aberrant IN multimerization with different mechanisms. Furthermore, recent discoveries unveiled that IN has an under-studied yet equally vital second function. This involves IN binding to the RNA genome in virions, necessary for proper virion maturation. In this work, we describe a series of quinolinonyl derivatives as inhibitors of both the IN catalytic functions and IN-RNA interactions, which impair both early and late steps of viral replication.

ACS Medicinal Chemistry LettersVol. 15(9)
University of Campania "Luigi Vanvitelli" (IT), Istituto Pasteur (IT), Sapienza University of Rome (IT), University of Colorado Denver (US)
European Commission, Ministero dell'Università e della Ricerca
Good health and well-being
Openalex Percentile: Top 84%
HIV/AIDS drug development and treatment
DOIOpen Access PDFOpenAlex
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