8GJT

Crystal Structure of HIV-1 LM/HT Clade A/E CRF01 GP120 Core in Complex with TFH-I-116-D1

Summary for 8GJT

• Entry DOI: 10.2210/pdb8gjt/pdb
• Descriptor: HIV-1 LM/HT Clade A/E CRF01 gp120 core, 2-acetamido-2-deoxy-beta-D-glucopyranose, (3S)-N-(4-chloro-3-fluorophenyl)-1-[(3R,5S)-3,4,5-trimethylpiperazine-1-carbonyl]piperidine-3-carboxamide, ... (5 entities in total)
• Functional Keywords: hiv-1 gp120, clade a/e cf01, viral protein-inhibitor complex, viral protein/inhibitor
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 1
• Total formula weight: 42363.50

Authors

Tolbert, W.D.,Nguyen, D.N.,Pazgier, M. (deposition date: 2023-03-16, release date: 2023-06-07, Last modification date: 2024-10-30)

Primary citation

Ding, S.,Tolbert, W.D.,Zhu, H.,Lee, D.,Marchitto, L.,Higgins, T.,Zhao, X.,Nguyen, D.,Sherburn, R.,Richard, J.,Gendron-Lepage, G.,Medjahed, H.,Mohammadi, M.,Abrams, C.,Pazgier, M.,Smith III, A.B.,Finzi, A.
Piperidine CD4-Mimetic Compounds Expose Vulnerable Env Epitopes Sensitizing HIV-1-Infected Cells to ADCC.
Viruses, 15:-, 2023

PubMed Abstract: The ability of the HIV-1 accessory proteins Nef and Vpu to decrease CD4 levels contributes to the protection of infected cells from antibody-dependent cellular cytotoxicity (ADCC) by preventing the exposure of Env vulnerable epitopes. Small-molecule CD4 mimetics (CD4mc) based on the indane and piperidine scaffolds such as (+)-BNM-III-170 and ()-MCG-IV-210 sensitize HIV-1-infected cells to ADCC by exposing CD4-induced (CD4i) epitopes recognized by non-neutralizing antibodies that are abundantly present in plasma from people living with HIV. Here, we characterize a new family of CD4mc, ()-MCG-IV-210 derivatives, based on the piperidine scaffold which engages the gp120 within the Phe43 cavity by targeting the highly conserved Asp Env residue. We utilized structure-based approaches and developed a series of piperidine analogs with improved activity to inhibit the infection of difficult-to-neutralize tier-2 viruses and sensitize infected cells to ADCC mediated by HIV+ plasma. Moreover, the new analogs formed an H-bond with the α-carboxylic acid group of Asp, opening a new avenue to enlarge the breadth of this family of anti-Env small molecules. Overall, the new structural and biological attributes of these molecules make them good candidates for strategies aimed at the elimination of HIV-1-infected cells.

PubMed: 37243271
DOI: 10.3390/v15051185

Experimental method

X-RAY DIFFRACTION (3.5 Å)