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

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Uittreksel

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.
TaalEngels
TijdschriftJ Med Chem
Volume56
Exemplaarnummer12
Pagina's (van-tot)5033-5047
Aantal pagina's15
ISSN0022-2623
DOI's
StatusGepubliceerd - 2013

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