title: Design, synthesis and evaluation of small molecule CD4-mimics as entry inhibitors possessing broad spectrum anti-HIV-1 activity.
abstract: Since our first discovery of a CD4-mimic, NBD-556, which targets the Phe43 cavity of HIV-1 gp120, we and other groups made considerable progress in designing new CD4-mimics with viral entry-antagonist property. In our continued effort to make further progress we have synthesized twenty five new analogs based on our earlier reported viral entry antagonist, NBD-11021. These compounds were tested first in HIV-1 Env-pseudovirus based single-cycle infection assay as well as in a multi-cycle infection assay. Four of these new compounds showed much improved antiviral potency as well as cytotoxicity. We selected two of the best compounds 45A (NBD-14009) and 46A (NBD-14010) to test against a panel of 51 Env-pseudotyped HIV-1 representing diverse subtypes of clinical isolates. These compounds showed noticeable breadth of antiviral potency with IC50of as low as 150nM. These compounds also inhibited cell-to-cell fusion and cell-to-cell HIV-1 transmission. The study is expected to pave the way of designing more potent and selective HIV-1 entry inhibitors targeted to the Phe43 cavity of HIV-1 gp120.
authors.affiliation: Laboratory of Molecular Modeling and Drug Design, Lindsey F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Curreli
authors.affiliation: EDASA Scientific, Scientific Park, Moscow State University, Leninskie Gory, Bld. 75, 77-101b, 119992 Moscow, Russia.
authors.forename: Dmitry S
authors.initials: DS
authors.lastname: Belov
authors.affiliation: Laboratory of Molecular Modeling and Drug Design, Lindsey F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA.
authors.forename: Ranjith R
authors.initials: RR
authors.lastname: Ramesh
authors.affiliation: Laboratory of Molecular Modeling and Drug Design, Lindsey F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA.
authors.forename: Naisargi
authors.initials: N
authors.lastname: Patel
authors.affiliation: EDASA Scientific, Scientific Park, Moscow State University, Leninskie Gory, Bld. 75, 77-101b, 119992 Moscow, Russia.
authors.forename: Andrea
authors.initials: A
authors.lastname: Altieri
authors.affiliation: EDASA Scientific, Scientific Park, Moscow State University, Leninskie Gory, Bld. 75, 77-101b, 119992 Moscow, Russia.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Kurkin
authors.affiliation: Laboratory of Molecular Modeling and Drug Design, Lindsey F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA.
authors.forename: Asim K
authors.initials: AK
authors.lastname: Debnath
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; C000603350:NBD-11021; D011758:Pyrroles; D054852:Small Molecule Libraries; D013844:Thiazoles
keywords: Broad spectrum; ENV-pseudovirus; HIV-1; Structure–activity relationship; Virus entry antagonist