# Ubiquitin Regulation of K Channels in Health and Disease

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $337,499

## Abstract

Summary
This proposal is for a COVID-19-related Administrative Supplement for RO1HL142111, “Ubiquitin regulation of
K Channels in Health and Disease”. We propose to adapt/apply tools and approaches including, nanobody
development and optical assays of membrane proteins, that we have developed for studies in the parent proposal
to develop novel solutions for COVID-19. There is an ongoing global pandemic in which a novel Coronavirus,
SARS-CoV-2, causes Coronavirus Disease-2019 (COVID-19) that is lethal to a subset of the infected population.
To date, there are >1.5 million confirmed COVID-19 cases worldwide with >70,000 fatalities. In the United States,
best case scenario projections indicate 100,000 – 240,000 lives will be lost to COVID-19, with a worst case
scenario of >2 million deaths. The current pandemic follows two other regional outbreaks of coronaviruses
responsible for severe acute respiratory syndrome (SARS-CoV) in 2002, and Middle Eastern respiratory
syndrome (MERS-CoV) in 2012, that caused epidemics with fatality rates of 10% and 36%, respectively. All three
coronaviruses represent examples of animal to human transmission of infection. Given a high zoonotic reservoir
of novel coronaviruses and persistence of close animal/human contact in various parts of the world, the chances
of future viral epidemics/pandemics beyond the current crisis is high. Hence, fatal diseases caused by viral
infections represent current and future widespread public health challenges, highlighting an urgent need for
general strategies that can combat not only COVID-19 but also other future viral outbreaks. SARS-CoV-2 is an
enveloped virus that gains access to host cells by using a receptor binding domain (RBD) on a viral surface spike
protein (S) to bind to membrane-bound angiotensin-converting enzyme 2 (ACE2) receptors on target cells.
Preventing the SARS-CoV-2 S protein/ACE2 receptor interaction is the main principle behind the beneficial
effects of neutralizing antibodies in recovered patients, and the scientific premise for an ongoing clinical trial for
administration of soluble ACE2 ectodomain. There are ongoing efforts to develop neutralizing monoclonal
antibodies (mAb) against SARS-CoV-2 S protein that disrupt interaction with ACE2. While potentially effective,
limitations of this approach include high cost, time-consuming, incompatibility with inhalation formulations, and
potential for viral mutations that result in escape from mAb-mediated neutralization. This proposal is based on
the hypothesis that engineered single-domain antibodies (nanobodies) with high avidity for SARS-CoV-2 S
protein can be generated to overcome some of the limitations of neutralizing mAbs and provide potential
therapeutic leads for COVID-19. We propose three aims: 1) Isolate and characterize neutralizing and non-
neutralizing nanobodies against SARS-CoV-2 S protein; 2) Develop cell-based high throughput fluorescence
assay to probe SARS-CoV-2 S protein/ACE2 interaction and inter...

## Key facts

- **NIH application ID:** 10143853
- **Project number:** 3R01HL142111-03S1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Henry M. Colecraft
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $337,499
- **Award type:** 3
- **Project period:** 2018-04-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10143853

## Citation

> US National Institutes of Health, RePORTER application 10143853, Ubiquitin Regulation of K Channels in Health and Disease (3R01HL142111-03S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10143853. Licensed CC0.

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