Lee Daniel, Niu Ling, Ding Shilei, Zhu Huile, Tolbert William D, Medjahed Halima, Beaudoin-Bussières Guillaume, Abrams Cameron, Finzi Andrés, Pazgier Marzena, Smith Amos B
Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
Infectious Disease Division, Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, United States.
ACS Med Chem Lett. 2024 Oct 28;15(11):1961-1969. doi: 10.1021/acsmedchemlett.4c00403. eCollection 2024 Nov 14.
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 β loop and the α-helix lead to improved antiviral activity.
HIV-1辅助蛋白Nef和Vpu降低CD4的能力，通过限制易损表位暴露于包膜糖蛋白（Env），保护受感染细胞免受抗体依赖性细胞毒性（ADCC）作用。基于哌啶支架的小分子CD4模拟物（CD4mcs）代表了一类新的药物，能够通过在Env上暴露CD4诱导（CD4i）表位，使HIV-1感染细胞对ADCC敏感，这些表位可被HIV感染者血浆中丰富的非中和抗体识别。在此，我们采用平行合成、基于结构的设计和优化相结合的方法，生成了一系列新的基于哌啶的CD4mcs，它们使HIV-1感染细胞对ADCC活性敏感。对gp120残基内CD4mcs的X射线晶体学研究表明，CD4mc在Phe43腔内的定位以及CD4mc与β环和α螺旋的协同接触导致抗病毒活性提高。
