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

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dc.contributor.author Morellato-Castillo, L. en_US
dc.contributor.author Acharya, P. en_US
dc.contributor.author Combes, O. en_US
dc.contributor.author Michiels, J. en_US
dc.contributor.author Descours, A. en_US
dc.contributor.author Ramos, O. H. en_US
dc.contributor.author Yang, Y. en_US
dc.contributor.author Vanham, G. en_US
dc.contributor.author Ariën, K. K. en_US
dc.contributor.author Kwong, P. D. en_US
dc.contributor.author Martin, L. en_US
dc.contributor.author Kessler, P. en_US
dc.date.accessioned 2014-09-25T13:39:27Z
dc.date.available 2014-09-25T13:39:27Z
dc.date.issued 2013 en_US
dc.identifier.issn 0022-2623 en_US
dc.identifier.doi http://dx.doi.org/10.1021/jm4002988 en_US
dc.identifier.other ITG-B4B; ITG-B8A; ITG-B9A; DBM; U-VIROL; JIF; DOI; Abstract; UPD56 en_US
dc.identifier.uri http://hdl.handle.net/10390/7641
dc.description.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. en_US
dc.language English en_US
dc.subject Viral diseases en_US
dc.subject HIV-1 en_US
dc.subject AIDS en_US
dc.subject Proteins en_US
dc.subject GP120 en_US
dc.subject Receptors en_US
dc.subject CD4 en_US
dc.subject Amino acids en_US
dc.subject Affinity en_US
dc.subject MiniCD4 en_US
dc.subject Neutralization en_US
dc.subject Interfaces en_US
dc.title Interfacial cavity filling to optimize CD4-mimetic miniprotein interactions with the HIV-1 surface protein en_US
dc.type Article en_US
dc.citation.issue 12 en_US
dc.citation.jtitle Journal of Medicinal Chemistry en_US
dc.citation.volume 56 en_US
dc.citation.pages 5033-5047 en_US
dc.identifier.pmid http://www.ncbi.nlm.nih.gov/pubmed/23710622 en_US
dc.citation.jabbreviation J Med Chem en_US


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