# DRUG DISCOVERY BY DIRECTED EVOLUTION IN MAMMALIAN CELLS

> **NIH NIH K99** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $98,161

## Abstract

Project Summary
Directed evolution, which adopts principles of natural evolution to the laboratory, is singular in its impact on
molecular engineering. As one example, it is responsible for the generation of the majority of approved
therapeutic antibodies and those still in clinical development. Despite its progress, a valuable therapeutic niche
remains outside its scope: the mammalian cell. While in vitro systems, phage, bacteria, and yeast have lent
themselves to laboratory manipulation, mammalian cells have proven less tractable. Consequently, the power
of evolution remains inaccessible to drug development pipelines that seek to modulate mammalian cell
signaling. Further, many directed evolution campaigns result in biomolecules that fail in critical ways when
transplanted to human cells. To address these limitations and advance methods in drug discovery, I will
explore and mine viral diversity to create a novel system for molecular evolution in mammalian cells. Next,
focusing on the 5-HT2A serotonin receptor, I will create extracellular nanobodies to template a drug discovery
campaign via structural determination and in silico docking. The insights gained by these studies will be
applied toward the directed evolution of state-specific nanobodies against dark GPCRs. This work will result in
a general method for directed evolution in mammalian cells, chemical matter against HTR2A, and new paths
forward for the deorphanization of GPCRs.

## Key facts

- **NIH application ID:** 10909940
- **Project number:** 5K99GM149931-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Daniel Dewran Kocak
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $98,161
- **Award type:** 5
- **Project period:** 2023-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10909940

## Citation

> US National Institutes of Health, RePORTER application 10909940, DRUG DISCOVERY BY DIRECTED EVOLUTION IN MAMMALIAN CELLS (5K99GM149931-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10909940. Licensed CC0.

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