# COVID19: Optimized Endosome-Targeting Compounds for SARS-CoV-2 and Emerging Coronaviruses

> **NIH VA I01** · PORTLAND VA MEDICAL CENTER · 2022 · —

## Abstract

COVID-19 is a global health crisis that must be countered with the full capacity of government
agencies, the private sector and the scientific community. New drugs that are broadly effective against
coronaviruses are a crucial tool for ending this pandemic and preventing future coronavirus pandemics.
Veterans are particularly at risk for severe COVID-19 due to older age and higher rates of cardiovascular
disease. Initial efforts to repurpose drugs for COVID-19 have revived interest in the antiviral activity of the 4-
aminoquinolines: chloroquine and hydroxychloroquine. Chloroquine has shown promise as an antiviral against
many pathogenic viruses in past preclinical studies, but these results have not translated into clinical benefit.
Initial clinical observations in China suggested that hydroxychloroquine may improve clinical outcomes, but as
of yet, this evidence remains inconclusive. Overall, chloroquine’s broad antiviral activity indicates a promising
antiviral mechanism that should be optimized by evaluating mechanistically similar compounds that target
intracellular endosomes that are essential for viral pathogenesis.
 This research proposal will test a focused chemical library of 4-aminoquinolines and aminoacridones
that are mechanistically similar to hydroxychloroquine against SARS-CoV-2 and related human coronaviruses.
These compounds were designed to have less cardiac toxicity than chloroquine and enhanced accumulation in
the Plasmodium digestive vacuole; properties that will likely lead to greater antiviral efficacy by creating higher
drug concentrations in the intracellular endosomes that viruses require for host cell entry. Initial antiviral testing
will both identify hits for preclinical evaluation and prioritization, and provide an extensive structure-activity-
relationship to guide synthesis of new compounds with greater antiviral potency. The most potent compounds
that are not toxic to human cells will be tested for target specificity, cardiac toxicity, and pharmacokinetic
feasibility. The early lead compounds from these studies will be rapidly advanced to testing in animal models of
SARS-CoV-2, other pathogenic coronaviruses and further preclinical testing via a separate funding
mechanism. For the structure-activity-relationship, computational pharmacophore modeling will use the results
of the initial antiviral testing, human cytotoxicity studies and target identification to identify structural features
that enhance antiviral activity. Based on these models, new antiviral 4-aminoquinolines will be created and
evaluated in the same manner as the hit compounds from the antiviral screen. This research will build on the
repurposed compound, hydroxychloroquine, to quickly identify endosome targeting antivirals with greater
clinical efficacy and safety for coronaviruses.

## Key facts

- **NIH application ID:** 10359085
- **Project number:** 5I01BX005434-02
- **Recipient organization:** PORTLAND VA MEDICAL CENTER
- **Principal Investigator:** Joseph Stone Doggett
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2021-04-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10359085

## Citation

> US National Institutes of Health, RePORTER application 10359085, COVID19: Optimized Endosome-Targeting Compounds for SARS-CoV-2 and Emerging Coronaviruses (5I01BX005434-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10359085. Licensed CC0.

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