# High-Throughput Platforms to Study Synthetic Receptors, Natural Molecules, and New Pathway Inhibitors

> **NIH NIH R35** · UNIVERSITY OF SOUTH FLORIDA · 2022 · $363,509

## Abstract

Project Summary
Advances in computational and experimental protein engineering have ushered in a new era of biomolecule
development, providing new functional binding proteins, improved enzymes, and rationally designed synthetic
receptors. Despite such progress, established techniques lack the ability to develop and study synthetic receptors
and inhibitory molecules in high throughput, instead relying on rational or function-agnostic engineering
approaches followed by low-throughput characterization for the desired activity. This deficiency in approach
results in 1) the development of suboptimal candidate proteins and 2) a costly development process.
My long-term goals are to 1) establish new platforms that incorporate protein function as a selective pressure
to engineer new molecules and 2) utilize these new platforms to understand the roles of natural and synthetic
proteins in cell signaling responses in both normal and disease pathologies. I hypothesize that the
incorporation of protein function as a selective pressure in protein engineering campaigns will result in the
efficient development of new classes of functional proteins capable of answering key biological questions. The
goals during this proposal period are to establish high-throughput screening platforms for inhibitor
engineering and for synthetic receptor engineering, as well as develop combined computational and
experimental protein engineering pipelines to aid the study of important proteins. Continued work in the
described areas has immense potential to aid the study of basic and synthetic biology through 1) greatly
expanding the availability of molecules to empower studies of the importance of individual molecules in cell
signaling responses, 2) providing a new toolkit for understanding synthetic receptor function, and 3) providing
modular platforms to aid discovery of functional engineered molecules. We will pursue three primary directions:
Direction 1: Establish a tethered inhibitor engineering platform with yeast surface display.
Current directed evolution approaches often lack protein function as a selective pressure, resulting in majority
development of passive binding proteins. We will incorporate the concept of tethering from the small molecule
screening community to drive yeast-displayed protein selection toward active inhibition.
Direction 2. Establish combined computational and experimental protein engineering pipelines.
Current protein engineering approaches typically rely on widespread mutagenesis or in-depth
computational/rational design to develop functional proteins. We will incorporate accessible computational
approaches for protein mutant library design and investigate these approaches for basic mutational studies.
Direction 3. Establish a high-throughput platform for studying synthetic receptors. Synthetic
receptors have made measurable impacts in both basic and clinical science, but no effective platform exists to
study their development in high throughput. We ...

## Key facts

- **NIH application ID:** 10500898
- **Project number:** 1R35GM147104-01
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** Lawrence A Stern
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $363,509
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10500898

## Citation

> US National Institutes of Health, RePORTER application 10500898, High-Throughput Platforms to Study Synthetic Receptors, Natural Molecules, and New Pathway Inhibitors (1R35GM147104-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10500898. Licensed CC0.

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