Project Details
Description
ABSTRACT
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of the current pandemic
of coronavirus disease 2019 (COVID-19), has posed an unprecedented global health threat in modern history.
While the approvals of vaccines, antibodies, and antiviral drug remdesivir have offered hope to end this
devastating pandemic, recent emergence and rapid spread of more infectious variants calls for renewed efforts
to develop effective therapies to combat SARS-CoV-2 infection. In SARS-CoV-2, the RNA 5′-cap structure is
methylated to ensure viral translation/replication and to evade host immune surveillance. We propose to discover
selective inhibitors of guanine N7-methyltransferase (N7-MTase, Nsp14) because the active site of Nsp14
MTase is uniquely constricted while human RNA capping MTases are overly open. Furthermore, the constricted
nature of the Nsp14 MTase active site has allowed us to design bi-substrate inhibitors. Our preliminary effort has
led to a nanomolar inhibitor that shows excellent anti-SARS-CoV-2 activity and no significant cytotoxicity. In this
application, we will perform lead optimization to improve the potency, selectivity and drug-like properties of our
Nsp14 MTase inhibitors, aiming to identify MTase inhibitors for use in future proof-of-concept studies in animal
models of SARS-CoV-2 infection. To accomplish the goal, we propose the following specific aims: Specific Aim
1. Design and synthesize SARS-CoV-2 Nsp14 MTase inhibitors and evaluate them in biochemical and antiviral
assays; Specific Aim 2. Assess selected SARS-CoV-2 Nsp14 MTase inhibitors for their physiochemical and in
vitro absorption, distribution, metabolism, excretion and toxicity (ADMET) properties; and Specific Aim 3.
Determine in vivo pharmacokinetics (PK) parameters of advanced SARS-CoV-2 Nsp14 MTase inhibitors. We
expect that the proposed research will significantly contribute to efforts in developing SARS-CoV-2 Nsp14 MTase
inhibitors as COVID-19 therapeutics.
Status | Active |
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Effective start/end date | 6/15/22 → 5/31/24 |
Funding
- National Institute of Allergy and Infectious Diseases: $193,750.00
- National Institute of Allergy and Infectious Diseases: $232,500.00
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