Optimization of a Piperidine CD4-Mimetic Scaffold Sensitizing HIV-1 Infected Cells to Antibody-Dependent Cellular Cytotoxicity

被引：0

作者：

Lee, Daniel ^{[1
]}

Niu, Ling ^{[3
]}

Ding, Shilei ^{[2
]}

Zhu, Huile ^{[1
]}

Tolbert, William D. ^{[3
]}

Medjahed, Halima ^{[2
]}

Beaudoin-Bussieres, Guillaume ^{[2
,4
]}

Abrams, Cameron ^{[5
]}

Finzi, Andres ^{[2
,4
]}

Pazgier, Marzena ^{[3
]}

Smith III, Amos B. ^{[1
]}

机构：

[1] Univ Penn, Sch Arts & Sci, Dept Chem, Philadelphia, PA 19104 USA

[2] Ctr Rech CHUM, Montreal, PQ H2X 0A9, Canada

[3] Uniformed Serv Univ Hlth Sci, Infect Dis Div, Dept Med, Bethesda, MD 20814 USA

[4] Univ Montreal, Dept Microbiol Infectiol & Immunol, 2950 Chemin Polytech, Montreal, PQ H3T 1J4, Canada

[5] Drexel Univ, Dept Chem & Biol Engn, Philadelphia, PA 19104 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2024年 / 15卷 / 11期

基金：

加拿大创新基金会; 美国国家卫生研究院;

关键词：

HIV; Antibody-dependent cellular cytotoxicity (ADCC); structure-activity relationship (SAR); smallmolecule CD4 mimetic compounds (CD4mc); gp120; CONFORMATION; EPITOPES;

D O I：

10.1021/acsmedchemlett.4c00403

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The ability of the HIV-1 accessory proteins Nef and Vpu to decrease CD4 protects infected cells from antibody-dependent cellular cytotoxicity (ADCC) by limiting the exposure of vulnerable epitopes to envelope glycoprotein (Env). Small-molecule CD4 mimetics (CD4mcs) based on piperidine scaffolds represent a new family of agents capable of sensitizing HIV-1-infected cells to ADCC by exposing CD4-induced (CD4i) epitopes on Env that are recognized by non-neutralizing antibodies which are abundant in plasma of people living with HIV. Here, we employed the combined methods of parallel synthesis, structure-based design, and optimization to generate a new line of piperidine-based CD4mcs, which sensitize HIV-1 infected cells to ADCC activity. The X-ray crystallographic study of the CD4mcs within the gp120 residues suggests that the positioning of the CD4mc inside the Phe43 cavity and synergistic contact of the CD4mc with the beta 20-21 loop and the alpha 1-helix lead to improved antiviral activity.

引用

页码：1961 / 1969

页数：9

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