Quinolinonyl Derivatives As Dual Inhibitors of the HIV-1 Integrase Catalytic Site and Integrase-RNA Interactions

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2024 Sep 18

PMID 39291012

Authors

Elisa Patacchini

Valentina Noemi Madia

Aurora Albano

Giuseppe Ruggieri

Antonella Messore

Davide Ialongo

Francesco Saccoliti

Luigi Scipione

Sandro Cosconati

Pratibha C Koneru

Reed Haney

Mamuka Kvaratskhelia

Roberto Di Santo

Roberta Costi

Affiliations

Soon will be listed here.

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.

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