title: Synthesis, 2D-NMR and molecular modelling studies of pentacycloundecane lactam-peptides and peptoids as potential HIV-1 wild type C-SA protease inhibitors.
abstract: In this study, eight non-natural peptides and peptoids incorporating the pentacycloundecane (PCU) lactam were designed and synthesized as potential inhibitors of the wild type C-SA HIV-protease. Five of these inhibitors gave IC(50) values ranging from 0.5 up to 0.75 µM against the resistance-prone wild type C-South African HIV-protease. NMR EASY-ROESY studies enabled us to describe the secondary structure of three of these compounds in solution. The 3D structures of the selected cage peptides were also modelled in solution using QM/MM/MD simulations. Satisfactory agreement between the NMR observations and the low energy calculated structures exists. Only one of these inhibitors (11 peptoid), which showed the best IC(50)(0.5 µM), exhibited a definable 3-D structure in solution. Autodock4 and AutodockVina were used to model the potential interaction between these inhibitors and the HIV-PR. It appears that the docking results are too crude to be correlated with the relative narrow range of experimental IC(50) values (0.5-10 µM). The PCU-peptides and peptoides were several orders less toxic (145 μM for 11 and 102 μM for 11 peptoid) to human MT-4 cells than lopinavir (0.025 μM). This is the first example of a polycyclic cage framework to be employed as an HIV-PR transition state analogue inhibitor and can potentially be utilized for other diseases related proteases.  [Figure: see text].
authors.affiliation: School of Pharmacy and Pharmacology, Durban, South Africa.
authors.forename: Maya M
authors.initials: MM
authors.lastname: Makatini
authors.forename: Katja
authors.initials: K
authors.lastname: Petzold
authors.forename: Cláudio Nahum
authors.initials: CN
authors.lastname: Alves
authors.forename: Per I
authors.initials: PI
authors.lastname: Arvidsson
authors.forename: Bahareh
authors.initials: B
authors.lastname: Honarparvar
authors.forename: Patrick
authors.initials: P
authors.lastname: Govender
authors.forename: Thavendran
authors.initials: T
authors.lastname: Govender
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Kruger
authors.forename: Yasien
authors.initials: Y
authors.lastname: Sayed
authors.lastname: JerônimoLameira
authors.forename: Glenn E M
authors.initials: GE
authors.lastname: Maguire
authors.forename: Mahmoud E S
authors.initials: ME
authors.lastname: Soliman
mesh_terms: D002460:Cell Line / Q000187:drug effects; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007769:Lactams / Q000737:chemistry*; D061466:Lopinavir / Q000009:adverse effects / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D034444:Peptoids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D018675:Toxicity Tests
chemical_list: D017320:HIV Protease Inhibitors; D007769:Lactams; D010455:Peptides; D034444:Peptoids; D061466:Lopinavir; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1