title: Interfacial cavity filling to optimize CD4-mimetic miniprotein interactions with HIV-1 surface glycoprotein.
abstract: 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.
authors.affiliation: Service d'Ingénierie Moléculaire des Protéines, iBiTecS, CEA, F-91191 Gif-sur-Yvette, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Morellato-Castillo
authors.forename: Priyamvada
authors.initials: P
authors.lastname: Acharya
authors.forename: Olivier
authors.initials: O
authors.lastname: Combes
authors.forename: Johan
authors.initials: J
authors.lastname: Michiels
authors.forename: Anne
authors.initials: A
authors.lastname: Descours
authors.forename: Oscar H P
authors.initials: OH
authors.lastname: Ramos
authors.forename: Yongping
authors.initials: Y
authors.lastname: Yang
authors.forename: Guido
authors.initials: G
authors.lastname: Vanham
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Ariën
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
authors.forename: Loïc
authors.initials: L
authors.lastname: Martin
authors.forename: Pascal
authors.initials: P
authors.lastname: Kessler
mesh_terms: D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology* / Q000633:toxicity; D001667:Binding, Competitive; D015704:CD4 Antigens / Q000737:chemistry*; D002460:Cell Line; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology* / Q000633:toxicity; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D010446:Peptide Fragments; C514793:gp120 protein, Human immunodeficiency virus 1