Synthetic Natural Product Inspired Cyclic Peptides for Discovery of Bioactive Natural Products and Biocatalysts
SESSION 8: NATURAL PRODUCT BIOSYNTHESIS & INSPIRATION FROM NATURE
Tuesday, June 27, 2023, at 11:45 am - 12:10 am
Natural products, NPs, are a bountiful source of medicines, agricultural products, and chemical tools. Bioinformatics data suggest hundreds-of-thousands of novel NPs remain to be discovered from Streptomyces. Unfortunately, many NPs are not produced under standard laboratory conditions. We are developing methods to access NPs from cryptic biosynthetic gene clusters, BGCs, utilizing a combination of bioinformatics, synthetic chemistry, and biocatalysis.
We recently developed SNaPP, Synthetic Natural Product Inspired Cyclic Peptides. SNaPP expedites bioactive molecule discovery by combining bioinformatics predictions of non-ribosomal peptide synthetases with chemical synthesis of the predicted natural products. SNaPP has enabled us to discover several interesting bioactive cyclic peptides. However, it also opened our eyes to the challenge of synthesizing small cyclic peptides.
Using the results from SNaPP, we identified PBP-like cyclases potentially capable of performing challenging cyclizations, such as for tetrapeptides. We have experimentally confirmed these activities and found one enzyme with a greatly expanded substrate scope that could have great utility as a biocatalyst.
Cancer is the second leading cause of death in the United States, and antibiotic resistant-bacteria are a growing health crisis. The discovery of novel chemotherapeutics and antibiotics is thus an area of great need. Natural products, NPs, have historically been a bountiful source of anticancer and antibiotic agents. Unfortunately, traditional means of discovering new bioactive NPs are no longer effective due to the problem of rediscovery. Novel strategies to find new bioactive NPs are desperately needed. Research in my group focuses on the discovery of new NPs from cryptic biosynthetic gene clusters, BGCs, and the examination of the anticancer and antibiotic activities of these NPs with a focus on difficult-to-hit targets. The major research areas in my lab are:
Chemicals induction of cryptic BGCs for the discovery of novel bioactive NPs
Synthesis of peptide macrocycles inspired by cryptic biosynthetic gene clusters
High throughput assays for challenging anticancer and antibacterial targets
These projects will establish general methods for the discovery of novel anticancer and antibiotic natural products from cryptic biosynthetic gene clusters. In the long term, this approach will allow discovery of many novel anticancer and antibiotic agents and could also be used for the discovery of other types of bioactive molecules. Students in my lab gain experience in organic synthesis, isolation of compounds from complex extracts, natural product structure elucidation, bacterial and mammalian cell culture, high throughput screening, target identification, and bioinformatics.