Interfacial cavity filling to optimize CD4-mimetic miniprotein interactions with HIV-1 surface glycoprotein.

Published

Journal Article

Ligand affinities can be optimized by interfacial cavity filling. A hollow (Phe43 cavity) between HIV-1 surface glycoprotein (gp120) and cluster of differentiation 4 (CD4) receptor extends beyond residue phenylalanine 43 of CD4 and cannot be fully accessed by natural amino acids. To increase HIV-1 gp120 affinity for a family of CD4-mimetic miniproteins (miniCD4s), we targeted the gp120 Phe43 cavity with 11 non-natural phenylalanine derivatives, introduced into a miniCD4 named M48 (1). The best derivative, named M48U12 (13), bound HIV-1 YU2 gp120 with 8 pM affinity and showed potent HIV-1 neutralization. It contained a methylcyclohexyl derivative of 4-aminophenylalanine, and its cocrystal structure with gp120 revealed the cyclohexane ring buried within the gp120 hydrophobic core but able to assume multiple orientations in the binding pocket, and the aniline nitrogen potentially providing a focus for further improvement. Altogether, the results provide a framework for filling the interfacial Phe43 cavity to enhance miniCD4 affinity.

Full Text

Duke Authors

Cited Authors

  • Morellato-Castillo, L; Acharya, P; Combes, O; Michiels, J; Descours, A; Ramos, OHP; Yang, Y; Vanham, G; Ariën, KK; Kwong, PD; Martin, L; Kessler, P

Published Date

  • June 27, 2013

Published In

Volume / Issue

  • 56 / 12

Start / End Page

  • 5033 - 5047

PubMed ID

  • 23710622

Pubmed Central ID

  • 23710622

Electronic International Standard Serial Number (EISSN)

  • 1520-4804

Digital Object Identifier (DOI)

  • 10.1021/jm4002988

Language

  • eng

Conference Location

  • United States