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 IC₅₀ 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 IC₅₀(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 IC₅₀ 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.

Graphical abstract: PCU-diastereomers peptide and peptoid inhibitors with arrows showing the observed EASY-ROESY correlations.

Keywords::

• Pentacycloundecane lactam-peptides
• peptoids
• HIV-1 wild type C-SA protease
• QM/MM/MD simulations
• molecular docking

Acknowledgements.

We thank Aspen Pharmacare, University of KwaZulu-Natal for financial support and the CHPC (HYPERLINK “http://www.chpc.ac.za” www.chpc.ac.za) for computational resources. We also thank Mr. Dilip Jagjivan (UKZN, South Africa) for his assistance with the NMR experiments. YS acknowledges the South African National Research Foundation (Thuthuka) for financial support.

Declaration of interest

This research was supported by NRF (SA) TG (GUN: 66319), KP (GUN: 69728), HGK and PIA (SA-Sweden bilateral grant), GEMM and CNA (IBSA). Financial support was provided by Aspen Pharmacare, University of KwaZulu-Natal and the computational resources by CHPC (HYPERLINK “http://www.chpc.ac.za” www.chpc.ac.za”).