An Isoquinoline Scaffold As a Novel Class of Allosteric HIV-1 Integrase Inhibitors

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2019 Feb 21

PMID 30783506

Citations 10

Authors

Tyler A Wilson

Pratibha C Koneru

Stephanie V Rebensburg

Jared J Lindenberger

Matthew J Kobe

Nicholas T Cockroft

Daniel Adu-Ampratwum

Ross C Larue

Mamuka Kvaratskhelia

James R Fuchs

Affiliations

Soon will be listed here.

Abstract

Allosteric HIV-1 integrase inhibitors (ALLINIs) are a new class of potential antiretroviral therapies with a unique mechanism of action and drug resistance profile. To further extend this class of inhibitors via a scaffold hopping approach, we have synthesized a series of analogues possessing an isoquinoline ring system. Lead compound binds in the v-shaped pocket at the IN dimer interface and is highly selective for promoting higher-order multimerization of inactive IN over inhibiting IN-LEDGF/p75 binding. Importantly, potently inhibited HIV-1 (A128T IN), which confers marked resistance to archetypal quinoline-based ALLINIs. Thermal degradation studies indicated that at elevated temperatures the acetic acid side chain of specific isoquinoline derivatives undergo decarboxylation reactions. This reactivity has implications for the synthesis of various ALLINI analogues.

Citing Articles

Structural aspects of HIV-1 integrase inhibitors: SAR studies and synthetic strategies.

Barik P, Gupta S, Singh G, Bharti S, Asati V Mol Divers. 2024; .

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Recent Developments in the Synthesis of HIV-1 Integrase Strand Transfer Inhibitors Incorporating Pyridine Moiety.

Starosotnikov A, Bastrakov M Int J Mol Sci. 2023; 24(11).

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Structure of a HIV-1 IN-Allosteric inhibitor complex at 2.93 Å resolution: Routes to inhibitor optimization.

Eilers G, Gupta K, Allen A, Montermoso S, Murali H, Sharp R PLoS Pathog. 2023; 19(3):e1011097.

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Multimodal Functionalities of HIV-1 Integrase.

Engelman A, Kvaratskhelia M Viruses. 2022; 14(5).

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Targeting the N-Terminus Domain of the Coronavirus Nucleocapsid Protein Induces Abnormal Oligomerization via Allosteric Modulation.

Hsu J, Chen J, Lin S, Hong J, Chen Y, Jeng U Front Mol Biosci. 2022; 9:871499.

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