title: Pentacycloundecane-diol-based HIV-1 protease inhibitors: biological screening, 2D NMR, and molecular simulation studies.
abstract: Novel compounds incorporating a pentacycloundecane (PCU) diol moiety were designed, synthesized, and evaluated as inhibitors of the wild-type C-South African (C-SA) HIV-1 protease. Seven compounds are reported herein, three of which displayed IC(50) values in the 0.5-0.6 μM range. The cytotoxicity of PCU cage peptides toward human MT-4 cells appears to be several orders of magnitude less toxic than the current antiviral medications ritonavir and lopinavir. NMR studies based on the observed through-space (1)H,(1)H distances/contacts in the EASY-ROESY spectra of three of the considered PCU peptide inhibitors enabled us to describe their secondary solution structure. Conserved hydrogen bonding interactions were observed between the hydroxy group of the PCU diol inhibitors and the catalytic triad (Asp25, Ile26, Gly27) of HIV protease in docking and molecular dynamics simulations. The biological significance and possible mode of inhibition by PCU-based HIV protease inhibitors discussed herein facilitates a deeper understanding of this family of inhibitors and their potential application to a vast number of alternative diseases related to proteases.
authors.affiliation: School of Chemistry, University of KwaZulu-Natal, Durban 4001, South Africa.
authors.forename: Bahareh
authors.initials: B
authors.lastname: Honarparvar
authors.forename: Maya M
authors.initials: MM
authors.lastname: Makatini
authors.forename: Sachin A
authors.initials: SA
authors.lastname: Pawar
authors.forename: Katja
authors.initials: K
authors.lastname: Petzold
authors.forename: Mahmoud E S
authors.initials: ME
authors.lastname: Soliman
authors.forename: Per I
authors.initials: PI
authors.lastname: Arvidsson
authors.forename: Yasien
authors.initials: Y
authors.lastname: Sayed
authors.forename: Thavendran
authors.initials: T
authors.lastname: Govender
authors.forename: Glenn E M
authors.initials: GE
authors.lastname: Maguire
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Kruger
mesh_terms: D000473:Alkanes / Q000737:chemistry*; D001665:Binding Sites; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary
chemical_list: D000473:Alkanes; D010455:Peptides; D011480:Protease Inhibitors; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; C022884:undecane