# Metal-binding Isosteres for Influenza Endonuclease Inhibitors and Beyond

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $340,957

## Abstract

PROJECT SUMMARY/ABSTRACT
 This research program is focused on developing new strategies for the discovery of metalloenzyme
inhibitors. Metalloenzymes are essential to numerous biological processes and are relevant to treating
diseases, including cancer, bacterial/viral infections, hypertension, and others. Despite the prevalence of
metalloenzymes (>40% of all enzymes are metalloenzymes) and their critical role in disease proliferation,
the development of new metalloenzyme inhibitors is extremely underexplored. The PI (Cohen) has
developed a research program that combines the principles of bioinorganic with medicinal chemistry and is
widely recognized as one of the few efforts focused on the challenges of metalloenzyme inhibition.
 Small molecules that inhibit metalloenzymes utilize a metal-binding pharmacophore (MBP) functional
group to bind to the active site metal ion(s) in the target. In the last project period, a focused MBP fragment
library for use in fragment-based drug discovery (FBDD) against metalloenzymes was assembled. In this
renewal application, the drug-like features of these MBP fragments will be improved by the application of
isostere replacement. This is expected to yield new chemical matter for identifying metalloenzyme
inhibitors, while accessing a wider range of physicochemical properties (e.g., acidity, lipophilicity) in these
scaffolds. These metal-binding isosteres (MBIs) will then be used to improve a class of highly active
inhibitors developed during the last project period against the influenza N-terminal endonuclease domain of
the polymerase acidic protein (PAN). Although active against PAN endonuclease, the poor uptake properties
of these inhibitors have led to suboptimal activity against the virus in cells. MBIs will be used to improve
physicochemical properties, while retaining enzyme-based activity, to produce highly active inhibitors
against the virus in live cells. Finally, to examine the on-target activity and selectivity of metalloenzyme
inhibitors, our MBPs, MBIs, and PAN inhibitors will be examined by Cellular Thermal Shift Assay (CETSA)
and affinity chromatography. These experiments will verify target engagement and evaluate how selectivity
improves as the MBP is developed into a full-length PAN endonuclease inhibitor. Detailed cellular target
engagement data using these methods for metalloenzyme inhibitors is scarce; therefore, these studies will
be valuable for clarifying the selectivity, and hence the clinical prospects, of these therapeutic compounds.
 The previous project period generated many collaborations, patent disclosures, conference
proceedings, and ~13 publications. In addition, skilled trainees for the biotechnology workforce were
mentored, and translation of our results into startup companies was achieved. We will continue to nurture
collaborations to discover best- and first-in-class metalloenzyme inhibitors that have the potential to improve
human health. Overall, this research program will c...

## Key facts

- **NIH application ID:** 9879893
- **Project number:** 9R01AI149444-09
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** SETH M COHEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $340,957
- **Award type:** 9
- **Project period:** 2020-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9879893

## Citation

> US National Institutes of Health, RePORTER application 9879893, Metal-binding Isosteres for Influenza Endonuclease Inhibitors and Beyond (9R01AI149444-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9879893. Licensed CC0.

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