Synthesis, 2D-NMR and molecular modelling studies of pentacycloundecane lactam-peptides and peptoids as potential HIV-1 wild type C-SA protease inhibitors. (February 2013)

• Record Type: Journal Article
• Authors: Makatini, Maya M.; Petzold, Katja; Alves, Cláudio Nahum; Arvidsson, Per I.; Honarparvar, Bahareh; Govender, Patrick; Govender, Thavendran; Kruger, Hendrik G.; Sayed, Yasien; JerônimoLameira, ; Maguire, Glenn E. M.; Soliman, Mahmoud E.S.
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 28:Number 1(2013:Feb.)
• Page Start: 78
• Page End: 88
• Publication Date: 2013-02
• Subjects: Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.3109/14756366.2011.633907
• Languages: English
• ISSNs: 1475-6366

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <p>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<sub>50</sub> 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 (<bold>11</bold> peptoid), which showed the best IC<sub>50</sub>(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<sub>50</sub> values (0.5–10 µM). The PCU-peptides and peptoides were several orders less toxic (145 μM for <bold>11</bold> and 102 μM for <bold>11</bold> 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.</p> </abstract>