# Modular synthesis of antibiotic and anticancer classes of natural products

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $84,553

## Abstract

Project Summary/Abstract
 This proposal summarizes ongoing projects in our laboratory focused on natural product classes that
have promising biological activity but are burdened with limitations that have prevented them from reaching their
therapeutic potential. These classes are structurally complex and modification of their is challenging by
semisynthetic and biosynthetic methods. We aim to develop fully synthetic routes to these classes from simple
building blocks, enabling chemical modification to overcome their limitations. These efforts are informed by
binding data (X-ray or cryo-EM) for each class. The primary goals of project outlined herein are to 1) expand
structure–function relationships for each of these important classes of molecules, and 2) discover potent analogs
that are suitable for hit-to-lead optimization or for use as tools to study biological systems. Additionally,
development of the synthetic routes themselves is highly innovative, and is often accompanied by development
of methods that are broadly applicable in chemistry. These efforts mirror our work on streptogramin and
lankacidin antibiotics, which was a primary focus in our Early Stage Investigator MIRA (R35GM128656), and led
to structural reassignments and to a potent hit compound with activity against resistant strains in vivo.
 Much of the biology for this work will be enabled by collaboration. Five of the projects summarized herein
focus on the development of novel antibiotics that target the ribosome and membrane proteins. Due to our
ongoing work in this area, we have several collaborations in place to evaluate the antimicrobial activity, in vivo
efficacy, and target engagement of new analogs. Beyond antibiotics, we propose to synthesize and derivatize
classes that target Hsp90, an anticancer target, and eEF1A, an anticancer and antiviral target. Evaluation of
these compounds for inhibitory activity, isoform selectivity, and binding will be enabled by new collaborations,
expanding the scope of our research. With chemical innovation paired with strong biological investigation, we
anticipate that the work outlined herein will lead to exciting discoveries in chemical synthesis and to the discovery
of hit compounds for the treatment of bacterial infections, cancer, and SARS-CoV-2.

## Key facts

- **NIH application ID:** 10878683
- **Project number:** 5R35GM148184-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Ian Bass Seiple
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $84,553
- **Award type:** 5
- **Project period:** 2023-08-01 → 2024-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10878683

## Citation

> US National Institutes of Health, RePORTER application 10878683, Modular synthesis of antibiotic and anticancer classes of natural products (5R35GM148184-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10878683. Licensed CC0.

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