Multi-Substituted Quinolines as HIV-1 Integrase Allosteric Inhibitors

被引：7

作者：

Long Phi Dinh ^{[1
]}

Sun, Jian ^{[2
]}

Glenn, Courtney D. ^{[1
]}

Patel, Krunal ^{[2
]}

Pigza, Julie A. ^{[2
]}

Donahue, Matthew G. ^{[2
]}

Yet, Larry ^{[1
]}

Kessl, Jacques J. ^{[2
]}

机构：

[1] Univ S Alabama, Dept Chem, Mobile, AL 36688 USA

[2] Univ Southern Mississippi, Dept Chem & Biochem, Hattiesburg, MS 39406 USA

来源：

VIRUSES-BASEL | 2022年 / 14卷 / 07期

基金：

美国国家卫生研究院; 美国国家科学基金会;

关键词：

HIV-1; integrase; ALLINI; quinolines; multimerization; ABERRANT PROTEIN MULTIMERIZATION; SMALL-MOLECULE INHIBITORS; LEDGF/P75; MECHANISM; SITE;

D O I：

10.3390/v14071466

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

Allosteric HIV-1 integrase (IN) inhibitors, or ALLINIs, are a new class of antiviral agents that bind at the dimer interface of the IN, away from the enzymatic catalytic site and block viral replication by triggering an aberrant multimerization of the viral enzyme. To further our understanding of the important binding features of multi-substituted quinoline-based ALLINIs, we have examined the IN multimerization and antiviral properties of substitution patterns at the 6 or 8 position. We found that the binding properties of these ALLINIs are negatively impacted by the presence of bulky substitutions at these positions. In addition, we have observed that the addition of bromine at either the 6 (6-bromo) or 8 (8-bromo) position conferred better antiviral properties. Finally, we found a significant loss of potency with the 6-bromo when tested with the ALLINI-resistant IN A128T mutant virus, while the 8-bromo analog retained full effectiveness.

引用

页数：13

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