title: Design, synthesis, and antiviral activity of entry inhibitors that target the CD4-binding site of HIV-1.
abstract: The CD4 binding site on HIV-1 gp120 has been validated as a drug target to prevent HIV-1 entry to cells. Previously, we identified two small molecule inhibitors consisting of a 2,2,6,6-tetramethylpiperidine ring linked by an oxalamide to a p-halide-substituted phenyl group, which target this site, specifically, a cavity termed "Phe43 cavity". Here we use synthetic chemistry, functional assessment, and structure-based analysis to explore variants of each region of these inhibitors for improved antiviral properties. Alterations of the phenyl group and of the oxalamide linker indicated that these regions were close to optimal in the original lead compounds. Design of a series of compounds, where the tetramethylpiperidine ring was replaced with new scaffolds, led to improved antiviral activity. These new scaffolds provide insight into the surface chemistry at the entrance of the cavity and offer additional opportunities by which to optimize further these potential-next-generation therapeutics and microbicides against HIV-1.
authors.affiliation: Lindsley F. Kimball Research Institute, New York Blood Center , 310 E. 67th Street, New York, New York 10065, United States.
authors.forename: Francesca
authors.initials: F
authors.lastname: Curreli
authors.forename: Spreeha
authors.initials: S
authors.lastname: Choudhury
authors.forename: Ilya
authors.initials: I
authors.lastname: Pyatkin
authors.forename: Victor P
authors.initials: VP
authors.lastname: Zagorodnikov
authors.forename: Anna Khulianova
authors.initials: AK
authors.lastname: Bulay
authors.forename: Andrea
authors.initials: A
authors.lastname: Altieri
authors.forename: Young Do
authors.initials: YD
authors.lastname: Kwon
authors.forename: Peter D
authors.initials: PD
authors.lastname: Kwong
authors.forename: Asim K
authors.initials: AK
authors.lastname: Debnath
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015704:CD4 Antigens / Q000378:metabolism*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D015195:Drug Design; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D010070:Oxalates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D000577:Amides; D019380:Anti-HIV Agents; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D010070:Oxalates; D010880:Piperidines; D013844:Thiazoles