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.
This study isolated and identified endophytic bacteria from the leaves of Crinum macowanii and investigated the potential of the bacterial endophyte extracts as antibacterial and anticancer agents and their subsequent secondary metabolites. Ethyl acetate extracts from the endophytes and the leaves (methanol: dichloromethane (1 : 1)) were used for antibacterial activity against selected pathogenic bacterial strains by using the broth microdilution method. The anticancer activity against the U87MG glioblastoma and A549 lung carcinoma cells was determined by the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay. Bacterial endophytes that were successfully isolated from C. macowanii leaves include Raoultella ornithinolytica, Acinetobacter guillouiae, Pseudomonas sp., Pseudomonas palleroniana, Pseudomonas putida, Bacillus safensis, Enterobacter asburiae, Pseudomonas cichorii, and Arthrobacter pascens. Pseudomonas cichorii exhibited broad antibacterial activity against both Gram-negative and Gram-positive pathogenic bacteria while Arthrobacter pascens displayed the least MIC of 0.0625 mg/mL. Bacillus safensis crude extracts were the only sample that showed notable cell reduction of 50% against A549 lung carcinoma cells at a concentration of 100 μg/mL. Metabolite profiling of Bacillus safensis, Pseudomonas cichorii, and Arthrobacter pascens crude extracts revealed the presence of known antibacterial and/or anticancer agents such as lycorine (1), angustine (2), crinamidine (3), vasicinol (4), and powelline. It can be concluded that the crude bacterial endophyte extracts obtained from C. macowanii leaves can biosynthesize bioactive compounds and can be bioprospected for medical application into antibacterial and anticancer agents.
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].
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