Interfacial cavity filling to optimize CD4-mimetic miniprotein interactions with the HIV-1 surface protein

L. Morellato-Castillo, P. Acharya, O. Combes, J. Michiels, A. Descours, O.H. Ramos, Y. Yang, G. Vanham, K.K. Ariën, P.D. Kwong, L. Martin, P. Kessler

Research output: Contribution to journalA1: Web of Science-article

Abstract

Ligand affinities can be optimized by interfacial cavity filling. A hollow (Phe43 cavity) between HIV-1 surface protein (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 eleven non-natural phenylalanine derivatives, introduced into a miniCD4 named M48 (1). The best derivative named M48U12 (13) binds HIV-1 YU2 gp120 with 8 pM affinity, and shows potent HIV-1 neutralization. It contained a methylcyclohexyl derivative of 4-aminophenylalanine and its co-crystal structure with gp120 revealed the cyclohexane ring buried within the gp120 hydrophobic core but able to assume multiple orientations in the binding pocket, and an 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.
Original languageEnglish
JournalJ Med Chem
Volume56
Issue number12
Pages (from-to)5033-5047
Number of pages15
ISSN0022-2623
DOIs
Publication statusPublished - 2013

Keywords

  • Viral diseases
  • HIV-1
  • AIDS
  • Proteins
  • GP120
  • Receptors
  • CD4
  • Amino acids
  • Affinity
  • MiniCD4
  • Neutralization
  • Interfaces

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