title: Pentacycloundecane-based inhibitors of wild-type C-South African HIV-protease.
abstract: In this study, we present the first account of pentacycloundecane (PCU) peptide based HIV-protease inhibitors. The inhibitor exhibiting the highest activity made use of a natural HIV-protease substrate peptide sequence, that is, attached to the cage (PCU-EAIS). This compound showed nanomolar IC(50) activity against the resistance-prone wild type C-South African HIV-protease (C-SA) catalytic site via a norstatine type functional group of the PCU hydroxy lactam. NMR was employed to determine a logical correlation between the inhibitory concentration (IC(50)) results and the 3D structure of the corresponding inhibitors in solution. NMR investigations indicated that the activity is related to the chirality of the PCU moiety and its ability to induce conformations of the coupled peptide side chain. The results from docking experiments coincided with the experimental observed activities. These findings open up useful applications for this family of cage peptide inhibitors, considering the vast number of alternative disease related proteases that exist.
authors.affiliation: School of Pharmacy and Pharmacology, University of KwaZulu-Natal, Durban 4001, South Africa.
authors.forename: Maya M
authors.initials: MM
authors.lastname: Makatini
authors.forename: Katja
authors.initials: K
authors.lastname: Petzold
authors.forename: Shimoga N
authors.initials: SN
authors.lastname: Sriharsha
authors.forename: Mahmoud E S
authors.initials: ME
authors.lastname: Soliman
authors.forename: Bahareh
authors.initials: B
authors.lastname: Honarparvar
authors.forename: Per I
authors.initials: PI
authors.lastname: Arvidsson
authors.forename: Yasien
authors.initials: Y
authors.lastname: Sayed
authors.forename: Patrick
authors.initials: P
authors.lastname: Govender
authors.forename: Glenn E M
authors.initials: GE
authors.lastname: Maguire
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Kruger
authors.forename: Thavendran
authors.initials: T
authors.lastname: Govender
mesh_terms: D000473:Alkanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D020134:Catalytic Domain; D003198:Computer Simulation; D005838:Genotype; D006678:HIV / Q000201:enzymology* / Q000235:genetics; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D013019:South Africa
chemical_list: D000473:Alkanes; D017320:HIV Protease Inhibitors; D016333:HIV Protease; C022884:undecane