Rational Genome Mining for Anti-Chagas Disease Agents
Biochemistry
Final Report Abstract
Natural products are a prolific source of bioactive compounds. They have accounted for twothirds of all small molecule approved drugs in the last 33 years, by either being used directly or by inspiring the production of analogs. However, with the increasing number of known natural products, the reisolation rate of already known compounds has steadily been increasing over the last few years. In addition, it happens all too often that challenging genome mining or chemistry guided isolation approaches result in the discovery of biologically inactive natural products. The goal of the project was the incorporation of computational tools into the drug discovery pipeline to increase the chances of discovering new and bioactive natural products. Due to several throwbacks relating to the cyanobacterial genomes as well as the bioactivity testing against the Chagas parasite, the proposed genome mining approach is still under way. The low quality of environmental cyanobacterial DNA delayed the assembly of complete biosynthetic gene clusters from the DNA sequence. An alternative approach to use only cultured cyanobacteria and prioritize them based on the activity of the crude extracts against the Chagas parasite was interrupted due to unreliable assay results. Nevertheless, I was able to use molecular docking experiments to guide the synthesis of a natural product analog to produce a compound that is very selective for the parasitic 20S proteasome. Based on the natural product carmaphycin B, a highly active and selective antimalarial agent was developed. In addition, the discovery of two new natural products, namely tutuilamide A and B, which are highly potent and very selective elastase inhibitors with unusual structural features, gives us insights into the binding mode of this interesting compound class. Using a semisynthetic approach as well as X-ray crystallography, we are still investigating the molecular mechanisms of the elastase inhibition. Another new natural product, a complex 40-membered polyhydroxy macrolide that was isolated from a cyanobacterial collection from the Palmyra Atoll, shows potent activity against the malaria parasite as well as the leishmaniasis parasite and could therefore act as a lead compound to develop a new antiparasitic drug.
Publications
- Chemical Biology of Marine Cyanobacteria, in Chemical Biology of Natural Products (Edited by Newman D. J., Cragg G. M., and Grothaus P. G.), CRC Press, Boca Raton, 2017, 43–86
Keller L., Leão T., and Gerwick W. H.
- Development of a Potent Inhibitor of the Plasmodium Proteasome with Reduced Mammalian Toxicity, J. Med. Chem. 2017, 60 (15), 6721-6732
LaMonte G.M., Almaliti J., Bibo-Verdugo B., Keller L., Zou B.Y., Yang J., Antonova-Koch Y., Orjuela-Sanchez P., Boyle C.A., Vigil E., Wang L., Goldgof G.M., Gerwick L., O'Donoghue A.J., Winzeler E.A., Gerwick W.H., Ottilie S.
(See online at https://doi.org/10.1021/acs.jmedchem.7b00671)
