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A Genes-to-Molecules Platform for Expanding Natural Product Diversity
Phone: (858) 205-3154
Email: mark.burk@lassogen.com
Phone: (858) 824-1771
Email: cschilling@genomatica.com
Address:
Type: Nonprofit College or University
Project Summary
Natural products (NPs) and derivatives thereof provide a rich source of chemical matter for drug
discovery and development. Over the past 30 years, NP-derived drugs have accounted for more
than 35% of FDA approvals. Despite their demonstrated importance, development of new NPs
has slowed over the past 15 years due to the lack of efficient methods for discovery, production,
and optimization, coupled with the high rate of NP rediscovery using traditional bioassay-guided
isolation techniques. Recently, next generation sequencing and genome-mining algorithms
suggest that a wealth of uncharacterized natural products exist in Nature, revealing a vast
untapped source of chemical diversity and biological activity. To unlock the latent potential of NPs
predicted from genome-mining, our proposed Phase I study aims to develop an integrated high-
throughput (HT) technology platform for rapidly (1) identifying, (2) synthesizing, and (3) screening
new NPs. In Phase II, this technology platform will be automated with robotics to provide
unprecedented speed and throughput for NP discovery and optimization.
The utility of this integrated platform first will be demonstrated during Phase I using lasso peptides
as a representative NP class. Lasso peptides are ribosomally synthesized and post translationally
modified peptides (RiPPs) that display a unique folded topology that endows the compounds with
extraordinary stability and a myriad of promising biological activities. The aim of this proposal is
to develop a platform that will significantly expand the known repertoire of lasso peptides, analogs,
and targets. Genomic and metagenomic data mining will provide the sequence information
required for HT generation of lasso peptides that will be screened for biological activity (initially
antimicrobial). The proposed specific aims outlined below will be achieved through the
collaboration between Genomatica, Inc. and Dr. Douglas Mitchell at the University of Illinois at
Urbana-Champaign.Project Narrative
The proposed Phase I study aims to develop an integrated high-throughput technology platform
for rapidly (1) identifying, (2) synthesizing, and (3) screening new natural products predicted from
metagenomic data in order to unlock the latent potential of natural products.
* Information listed above is at the time of submission. *