Identification of clickable HIV-1 capsid-targeting probes for viral replication inhibition

被引：1

作者：

Mcfadden, William M. ^{[1
,2
]}

Casey-Moore, Mary C. ^{[3
,4
,11
]}

Bare, Grant A. L. ^{[5
,6
]}

Kirby, Karen A. ^{[1
,2
,3
,4
]}

Wen, Xin ^{[1
,2
]}

Li, Gencheng ^{[5
,6
]}

Wang, Hua ^{[5
,6
]}

Slack, Ryan L. ^{[1
,2
]}

Snyder, Alexa A. ^{[1
,2
]}

Lorson, Zachary C. ^{[1
,2
]}

Kaufman, Isabella L. ^{[1
,2
]}

Cilento, Maria E. ^{[1
,2
]}

Tedbury, Philip R. ^{[1
,2
,4
]}

Gembicky, Milan ^{[7
]}

Olson, Arthur J. ^{[8
]}

Torbett, Bruce E. ^{[9
,10
]}

Sharpless, Barry ^{[5
,6
]}

Sarafianos, Stefan G. ^{[1
,2
,3
,4
]}

机构：

[1] Emory Univ, Ctr ViroScience & Cure, Dept Pediat, Lab Biochem Pharmacol,Sch Med, 1760 Haygood Dr NE, Atlanta, GA 30322 USA

[2] Childrens Healthcare Atlanta, Atlanta, GA 30322 USA

[3] Univ Missouri, Christopher S Bond Life Sci Ctr, Columbia, MO 65211 USA

[4] Univ Missouri, Sch Med, Dept Mol Microbiol & Immunol, Columbia, MO 65212 USA

[5] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA

[6] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA

[7] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92521 USA

[8] Scripps Res Inst, Dept Integrat Struct & Computat Biol, La Jolla, CA 92037 USA

[9] Seattle Childrens Res Inst, Ctr Immun & Immunotherapies, Seattle, WA 98101 USA

[10] Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98101 USA

[11] CDCP, Atlanta, GA 30329 USA

来源：

CELL CHEMICAL BIOLOGY | 2024年 / 31卷 / 03期

基金：

美国国家卫生研究院;

关键词：

IMMUNODEFICIENCY-VIRUS TYPE-1; REVERSE-TRANSCRIPTASE; INTERSUBUNIT INTERACTIONS; PROTEIN; PREDICTION; CHEMISTRY; CELLS; SUFEX; SITE; FLUOROSULFATE;

D O I：

10.1016/j.chembiol.2024.02.012

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Of the targets for HIV -1 therapeutics, the capsid core is a relatively unexploited but alluring drug target due to its indispensable roles throughout virus replication. Because of this, we aimed to identify "clickable"covalent modifiers of the HIV -1 capsid protein (CA) for future functionalization. We screened a library of fluorosulfate compounds that can undergo sulfur(VI) fluoride exchange (SuFEx) reactions, and five compounds were identified as hits. These molecules were further characterized for antiviral effects. Several compounds impacted in vitro capsid assembly. One compound, BBS-103, covalently bound CA via a SuFEx reaction to Tyr145 and had antiviral activity in cell -based assays by perturbing virus production, but not uncoating. The covalent binding of compounds that target the HIV -1 capsid could aid in the future design of antiretroviral drugs or chemical probes that will help study aspects of HIV -1 replication.

引用

页码：477 / 486.e7

页数：18

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