Dataset Information

Design, synthesis and biological evaluation of indole-2-carboxylic acid derivatives as novel HIV-1 integrase strand transfer inhibitors.

ABSTRACT: Integrase plays an important role in the life cycle of HIV-1, and integrase strand transfer inhibitors (INSTIs) can effectively impair the viral replication. However, drug resistance mutations have been confirmed to decrease the efficacy of INSTI during the antiviral therapy. Herein, indole-2-carboxylic acid (1) was found to inhibit the strand transfer of integrase, and the indole nucleus of compound 1 was observed to chelate with two Mg²⁺ ions within the active site of integrase. Through optimization of compound 1, a series of indole-2-carboxylic acid derivatives were designed and synthesized, and compound 17a was proved to markedly inhibit the effect of integrase, with IC₅₀ value of 3.11 μM. Binding mode analysis of 17a demonstrated that the introduced C6 halogenated benzene ring could effectively bind with the viral DNA (dC20) through π-π stacking interaction. These results indicated that indole-2-carboxylic acid is a promising scaffold for the development of integrase inhibitors.

SUBMITTER: Zhang RH

PROVIDER: S-EPMC10945512 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Design, synthesis and biological evaluation of indole-2-carboxylic acid derivatives as novel HIV-1 integrase strand transfer inhibitors.

Zhang Rong-Hong RH Chen Guo-Qi GQ Wang Weilin W Wang Yu-Chan YC Zhang Wen-Li WL Chen Ting T Xiong Qian-Qian QQ Zhao Yong-Long YL Liao Shang-Gao SG Li Yong-Jun YJ Yan Guo-Yi GY Zhou Meng M

RSC advances 20240318 13

Integrase plays an important role in the life cycle of HIV-1, and integrase strand transfer inhibitors (INSTIs) can effectively impair the viral replication. However, drug resistance mutations have been confirmed to decrease the efficacy of INSTI during the antiviral therapy. Herein, indole-2-carboxylic acid (1) was found to inhibit the strand transfer of integrase, and the indole nucleus of compound 1 was observed to chelate with two Mg<sup>2+</sup> ions within the active site of integrase. Thr ...[more]

PMID: 38500630

Similar Datasets

Project description:More than fifteen million women with the human immunodeficiency virus type-1 (HIV-1) infection are of childbearing age world-wide. Due to improved and affordable access to antiretroviral therapy (ART), the number of in utero antiretroviral drug (ARV)-exposed children has exceeded a million and continues to grow. While most recommended ART taken during pregnancy suppresses mother to child viral transmission, the knowledge of drug safety linked to fetal neurodevelopment remains an area of active investigation. For example, few studies have suggested that ARV use can be associated with neural tube defects (NTDs) and most notably with the integrase strand transfer inhibitor (INSTI) dolutegravir (DTG). After risk benefit assessments, the World Health Organization (WHO) made recommendations for DTG usage as a first and second-line preferred treatment for infected populations including pregnant women and those of childbearing age. Nonetheless, long-term safety concerns remain for fetal health. This has led to a number of recent studies underscoring the need for biomarkers to elucidate potential mechanisms underlying long-term neurodevelopmental adverse events. With this goal in mind, we now report the inhibition of matrix metalloproteinases (MMPs) activities by INSTIs as an ARV class effect. Balanced MMPs activities play a crucial role in fetal neurodevelopment. Inhibition of MMPs activities by INSTIs during neurodevelopment could be a potential mechanism for adverse events. Thus, comprehensive molecular docking testing of the INSTIs, DTG, bictegravir (BIC), and cabotegravir (CAB), against twenty-three human MMPs showed broad-spectrum inhibition. With a metal chelating chemical property, each of the INSTI were shown to bind Zn++ at the MMP's catalytic domain leading to MMP inhibition but to variable binding energies. These results were validated in myeloid cell culture experiments demonstrating MMP-2 and 9 inhibitions by DTG, BIC and CAB and even at higher degree than doxycycline (DOX). Altogether, these data provide a potential mechanism for how INSTIs could affect fetal neurodevelopment.

Dataset Information

Design, synthesis and biological evaluation of indole-2-carboxylic acid derivatives as novel HIV-1 integrase strand transfer inhibitors.

Publications

Design, synthesis and biological evaluation of indole-2-carboxylic acid derivatives as novel HIV-1 integrase strand transfer inhibitors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets