# Molecular Prosthetics and Lego Chemistry

> **NIH NIH R35** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2023 · $716,136

## Abstract

Project Summary/Abstract
This proposal aims to substantially advance two frontier research areas, Molecular Prosthetics and Automated
Small Molecule Synthesis, and thereby have a major impact on human health. The first half targets the
development of a new class of molecular prosthetics that replace missing biochemical reactions. Our lab has
recently demonstrated in animals and in people that small molecules can replace the function of deficient proteins,
thus operating as prostheses on the molecular scale. We further illuminated specific mechanisms that permit
imperfect functional mimicry to be sufficient for substantial physiology restoration due to the inherent robustness
of living systems. In this proposal we will launch a new research direction to find small molecules that replace
deficient enzymes. There are more than 100 human diseases linked to loss of enzyme function, and we will
specifically target three examples: Ornithine Transcarbamylase Deficiency, Argininosuccinate Lyase Deficiency,
and Hereditary Tyrosinemia Type 1. These diseases have two features in common that we propose render them
susceptible to this approach: 1) a high concentration of the substrate for the missing enzyme, or an upstream
precursor, builds up in the blood and/or tissues, and 2) the corresponding substrate has unique chemical
reactivity. We hypothesize that these two features will permit imperfect small molecule reagents to serve as
effective functional surrogates for missing enzymes in human blood plasma and in mouse models. The second
half targets new molecular lego kits for automated synthesis of two functionally-rich classes of natural products:
lipids and polycyclic terpenoids. Both classes perform many biological and industrial functions, yet remain
inherently challenging to synthesize. Building on our recent development of a fully automated lego-like platform
for small molecule synthesis, we plan to create a lego kits for on-demand preparation of both classes of
compounds. Parallel retrosynthetic analysis showed that preparation of ~130 known polyunsaturated fatty acids
requires only 26 building blocks, which we will prepare. We will also develop two new Csp3-C bond forming
methods to iteratively assemble building blocks, and a Nextgen synthesis machine to render this process fully
automated. We will apply this platform to better understand molecular prosthetic ion channels. We also plan to
combine modular lego-like construction of linear molecules with cyclization-promoting self-assembled
resorcinarene capsules to create a highly efficient and flexible lego kit for polycyclic terpenoids. To this end, we
will define new structure-cyclization relationships, characterize their underpinnings, and leverage them to achieve
efficient syntheses of complex polycyclic terpenoid natural products. Collectively these studies will push the
frontiers of chemical biology and organic synthesis and open new frontiers for medicine.

## Key facts

- **NIH application ID:** 10552238
- **Project number:** 2R35GM118185-06
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Martin D Burke
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $716,136
- **Award type:** 2
- **Project period:** 2016-06-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10552238

## Citation

> US National Institutes of Health, RePORTER application 10552238, Molecular Prosthetics and Lego Chemistry (2R35GM118185-06). Retrieved via AI Analytics 2026-06-24 from https://api.ai-analytics.org/grant/nih/10552238. Licensed CC0.

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