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Synthesis, 2D-NMR and molecular modelling studies of pentacycloundecane lactam-peptides and peptoids as potential HIV-1 wild type C-SA protease inhibitors
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
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2013 (English)In: Journal of enzyme inhibition and medicinal chemistry (Print), ISSN 1475-6366, E-ISSN 1475-6374, Vol. 28, no 1, 78-88 p.Article in journal (Refereed) Published
Abstract [en]

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 IC50 values ranging from 0.5 up to 0.75 mu M 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 IC50 (0.5 mu M), 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 IC50 values (0.5-10 mu M). The PCU-peptides and peptoides were several orders less toxic (145 mu M for 11 and 102 mu M for 11 peptoid) to human MT-4 cells than lopinavir (0.025 mu M). 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.

Place, publisher, year, edition, pages
2013. Vol. 28, no 1, 78-88 p.
Keyword [en]
pentacycloundecane lactam-peptides, peptoids, HIV-1 wild type C-SA protease, QM/MM/MD simulations, molecular docking
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-196021DOI: 10.3109/14756366.2011.633907ISI: 000313663400010OAI: oai:DiVA.org:uu-196021DiVA: diva2:609123
Available from: 2013-03-04 Created: 2013-03-04 Last updated: 2013-03-04Bibliographically approved

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Arvidsson, Per I.
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