Crystal structures of HIV-1 gp120 envelope glycoprotein in complex with NBD analogues that target the CD4-binding site.
Efforts to develop therapeutic agents that inhibit HIV-1 entry have led to the identification of several small molecule leads. One of the most promising is the NBD series, which binds within a conserved gp120 cavity and possesses para-halogen substituted aromatic rings, a central oxalamide linker, and a tetramethylpiperidine moiety. In this study, we characterized structurally the interactions of four NBD analogues containing meta-fluoro substitution on the aromatic ring and various heterocyclic ring replacements of the tetramethylpiperidine group. The addition of a meta-fluorine to the aromatic ring improved surface complementarity and did not alter the position of the analogue relative to gp120. By contrast, heterocyclic ring replacements of the tetramethylpiperidine moiety exhibited diverse positioning and interactions with the vestibule of the gp120 cavity. Overall, the biological profile of NBD-congeners was modulated by ligand interactions with the gp120-cavity vestibule. Herein, six co-crystal structures of NBD-analogues with gp120 provide a structural framework for continued small molecule-entry inhibitor optimization.
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
Young Do
YD
Kwon
Department of Chemistry, Bryn Mawr College, Bryn Mawr, Pennsylvania, United States of America.
Judith M
JM
LaLonde
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
Yongping
Y
Yang
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Mark A
MA
Elban
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Akihiro
A
Sugawara
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Joel R
JR
Courter
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
David M
DM
Jones
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Amos B
AB
Smith
Laboratory of Molecular Modeling and Drug Design, Lindsey F. Kimball Research Institute of the New York Blood Center, New York, New York, United States of America.
Asim K
AK
Debnath
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
Peter D
PD
Kwong
D001665:Binding Sites; D015704:CD4 Antigens / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D010070:Oxalates / Q000737:chemistry; D010880:Piperidines / Q000737:chemistry; D011485:Protein Binding
D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; C514247:N-(4-bromophenyl)-N'-(2,2,6,6-tetramethylpiperidin-4-yl)oxalamide; C514246:N-(4-chlorophenyl)-N'-(2,2,6,6-tetramethylpiperidin-4-yl)oxalamide; D010070:Oxalates; D010880:Piperidines; C514793:gp120 protein, Human immunodeficiency virus 1