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HIV-1 gp120-CXCR4 recognition probed with synthetic nanomolar affinity D-peptides containing fragments of gp120 V3 loop.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2022 Dec 15; Vol. 244, pp. 114797. Date of Electronic Publication: 2022 Sep 28. - Publication Year :
- 2022
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Abstract
- The human immunodeficiency virus type 1 (HIV-1) recognizes one of its principal coreceptors, the CXC chemokine receptor 4 (CXCR4) on the host cell via the third variable loop (V3 loop) of HIV-1 envelope glycoprotein gp120 during the viral entry process. Here, we investigated the stereochemical mechanism of the molecular recognition of HIV-1 gp120 V3 loop with coreceptor CXCR4 by using peptide probes containing important fragments of the V3 loop. The tip and base/stem fragments of the V3 loop critical for V3 loop function were linked individually with the fragment derived from another CXCR4's chemokine ligand, vMIP-II to generate nanomolar affinity peptide probes of the interactions of CXCR4-V3 loop fragments. When the amino acid residues of the V3 loop fragments in these combinational peptides were changed from L-to D-configurations, the resulting peptides remarkably retained or had even enhanced recognition by CXCR4 as shown by competitive ligand-receptor binding. The ability of these peptides, regardless of the different l- or d-amino acids used, in binding CXCR4 and antagonizing CXCR4 functions was demonstrated by their blockade of calcium influx, cell migration, and CXCR4 internalization triggered by the activation of CXCR4 signaling by its endogenous ligand SDF-1α. The structural mechanisms of CXCR4 interactions with these peptides were examined with site-directed mutagenesis and molecular modeling. These results indicate that CXCR4's interface with key segments of HIV-1 gp120 V3 loop is flexible in terms of stereospecificity of ligand-receptor interaction which may have implication on understanding the viral entry mechanism and how the virus evades immune detection with V3 loop mutations and retains effective recognition of the host cell's coreceptor.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Humans
Chemokine CXCL12 metabolism
Ligands
Receptors, CCR5 metabolism
HIV Envelope Protein gp120 chemistry
HIV-1 physiology
Peptide Fragments chemistry
Receptors, CXCR4 analysis
Receptors, CXCR4 chemistry
Receptors, CXCR4 genetics
Receptors, Virus chemistry
Receptors, Virus genetics
Virus Internalization
Molecular Probes chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 244
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 36270088
- Full Text :
- https://doi.org/10.1016/j.ejmech.2022.114797