# Non-Covalent Molecular Recognition for Drug Targeting in the Body

> **NIH NIH R35** · UNIVERSITY OF NOTRE DAME · 2021 · $383,425

## Abstract

PROJECT SUMMARY:
Even with an ever-expanding arsenal of active drug molecules validated in vitro, ensuring these reach their
desired target in the body, while at the same time limiting toxic exposure in healthy tissue, remains a challenge.
Routes for targeting drugs using antibodies or targeted carriers still result in less than 1% of drug arriving at the
site of need. Molecular-scale targeting may have inherent advantages relative to these approaches due to more
extensive tissue distribution and more rapid clearance of unbound attenuated therapeutic agents, leading to more
drug arriving at the site of need or clearing prior to onset of systemic toxicity. Routes using `click' chemistry and
related covalent ligations have been explored for homing drugs to pre-targeted sites. Here, we describe our
progress and plans in developing a versatile and modular molecular-scale approach that uses synthetic non-
covalent affinity to home drugs to desired sites in the body. Relative to covalent molecular-scale approaches, the
chemistry we use has faster kinetics of association and also enables future reuse of the targeted site. Through
prodrug methodology, we have shown that drugs of interest can be modified with affinity motifs through labile
linkers, to be recognized at desired tissue sites by the presence of a corresponding binding partner. Serial re-
dosing of these sites, or the possibility to temporally change the drug delivered, adds further benefit to our
modular non-covalent approach. With this proposal, we seek to further define this research program and more
fully capture the benefits of non-covalent recognition relative to `click'-based alternatives. Specifically, we will
elucidate the importance of prodrug design and pharmacokinetic properties. So as to enable serial re-targeting of
a drug site – a distinct benefit of non-covalent recognition – we will explore new chemistry for in situ immolation to
lower-binding variants. We will also explore this approach in overcoming common physiologic barriers to the
administration of protein and small molecule therapeutics, using the systemic administration of innocuous agents
to trigger the release of therapeutic compounds bearing affinity tags from locally applied depots. Finally, to
expand the therapeutic scenarios wherein this targeting route may be useful, we will explore this affinity axis for
integration with metabolically engineered cells. In summary, we are optimistic that the new targeting technology
we are developing will unlock the vast therapeutic potential of active agents which are presently limited by
systemic toxicity or poor target localization. A platform such as that we are pursuing would have broad application
in therapeutic delivery for the treatment of a variety of diseases or for remote intervention in implanted biomedical
device practice.

## Key facts

- **NIH application ID:** 10248517
- **Project number:** 5R35GM137987-02
- **Recipient organization:** UNIVERSITY OF NOTRE DAME
- **Principal Investigator:** Matthew Webber
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $383,425
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10248517

## Citation

> US National Institutes of Health, RePORTER application 10248517, Non-Covalent Molecular Recognition for Drug Targeting in the Body (5R35GM137987-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10248517. Licensed CC0.

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