8FLZ

HIV-1 gp120 complex with CJF-III-049-S

8FLZ の概要

• エントリーDOI: 10.2210/pdb8flz/pdb
• 関連するPDBエントリー: 8FLY
• 分子名称: Envelope glycoprotein gp120, 2-acetamido-2-deoxy-beta-D-glucopyranose, N~1~-{(1R,2R,3S)-2-(carbamimidamidomethyl)-3-[(3S)-3,4-dihydroxybutyl]-5-[(methylamino)methyl]-2,3-dihydro-1H-inden-1-yl}-N~2~-(4-chloro-3-fluorophenyl)ethanediamide, ... (4 entities in total)
• 機能のキーワード: retrovirus, gp120, entry inhibitor, structure-based drug design, small molecule, antiretroviral therapy, viral protein-inhibitor complex, viral protein/inhibitor
• 由来する生物種: HIV-1 06TG.HT008
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 166914.11

構造登録者

Gong, Z.,Hendrickson, W.A. (登録日: 2022-12-22, 公開日: 2023-04-05, 最終更新日: 2024-11-06)

主引用文献

Fritschi, C.J.,Anang, S.,Gong, Z.,Mohammadi, M.,Richard, J.,Bourassa, C.,Severino, K.T.,Richter, H.,Yang, D.,Chen, H.C.,Chiu, T.J.,Seaman, M.S.,Madani, N.,Abrams, C.,Finzi, A.,Hendrickson, W.A.,Sodroski, J.G.,Smith III, A.B.
Indoline CD4-mimetic compounds mediate potent and broad HIV-1 inhibition and sensitization to antibody-dependent cellular cytotoxicity.
Proc.Natl.Acad.Sci.USA, 120:e2222073120-e2222073120, 2023

PubMed Abstract: Binding to the host cell receptors, CD4 and CCR5/CXCR4, triggers large-scale conformational changes in the HIV-1 envelope glycoprotein (Env) trimer [(gp120/gp41)] that promote virus entry into the cell. CD4-mimetic compounds (CD4mcs) comprise small organic molecules that bind in the highly conserved CD4-binding site of gp120 and prematurely induce inactivating Env conformational changes, including shedding of gp120 from the Env trimer. By inducing more "open," antibody-susceptible Env conformations, CD4mcs also sensitize HIV-1 virions to neutralization by antibodies and infected cells to antibody-dependent cellular cytotoxicity (ADCC). Here, we report the design, synthesis, and evaluation of novel CD4mcs based on an indoline scaffold. Compared with our current lead indane scaffold CD4mc, BNM-III-170, several indoline CD4mcs exhibit increased potency and breadth against HIV-1 variants from different geographic clades. Viruses that were selected for resistance to the lead indane CD4mc, BNM-III-170, are susceptible to inhibition by the indoline CD4mcs. The indoline CD4mcs also potently sensitize HIV-1-infected cells to ADCC mediated by plasma from HIV-1-infected individuals. Crystal structures indicate that the indoline CD4mcs gain potency compared to the indane CD4mcs through more favorable π-π overlap from the indoline pose and by making favorable contacts with the vestibule of the CD4-binding pocket on gp120. The rational design of indoline CD4mcs thus holds promise for further improvements in antiviral activity, potentially contributing to efforts to treat and prevent HIV-1 infection.

PubMed: 36961924
DOI: 10.1073/pnas.2222073120

実験手法

X-RAY DIFFRACTION (2 Å)