Coronavirus helicases: attractive and unique targets of antiviral drug-development and therapeutic patents

ABSTRACT

Introduction: Coronaviruses encode a helicase that is essential for viral replication and represents an excellent antiviral target. However, only a few coronavirus helicase inhibitors have been patented. These patents include drug-like compound SSYA10-001, aryl diketo acids (ADK), and dihydroxychromones. Additionally, adamantane-derived bananins, natural flavonoids, one acrylamide derivative [(E)-3-(furan-2-yl)-N-(4-sulfamoylphenyl)acrylamide], a purine derivative (7-ethyl-8-mercapto-3-methyl-3,7-dihydro-1 H-purine-2,6-dione), and a few bismuth complexes. The IC₅₀ of patented inhibitors ranges between 0.82 μM and 8.95 μM, depending upon the assays used. Considering the urgency of clinical interventions against Coronavirus Disease-19 (COVID-19), it is important to consider developing antiviral portfolios consisting of small molecules.

Areas covered: This review examines coronavirus helicases as antiviral targets, and the potential of previously patented and experimental compounds to inhibit the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) helicase.

Expert opinion: Small molecule coronavirus helicase inhibitors represent attractive pharmacological modalities for the treatment of coronaviruses such as SARS-CoV and SARS-CoV-2. Rightfully so, the current emphasis is focused upon the development of vaccines. However, vaccines may not work for everyone and broad-based adoption of vaccinations is an increasingly challenging societal endeavor. Therefore, it is important to develop additional pharmacological antivirals against the highly conserved coronavirus helicases to broadly protect against this and subsequent coronavirus epidemics.

KEYWORDS:

• Helicase
• mers-CoV
• nsp13
• sars-CoV
• sars-CoV-2

Article highlights

• Overview of currently patented coronavirus helicase inhibitors.

• Overview of other compounds that inhibit nsp13.

• Inclusion of compounds that reflect structure activity relationship (SAR) of patented compound SSYA10–001.

• Overview of a strategy to identify new compounds related to the patented inhibitors.

• Challenges in designing nsp13 specific antiviral compounds.

• Expert opinion on future directions of the field. We suggested that SAR can be used to identify the compounds that may be better inhibitors of nsp13 than the patented compounds.

This box summarizes key points contained in the article.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Declaration of interest

K Singh serves as a consultant for Sanctum Therapeutics Corporation, Sunnyvale, CA, USA and has served as a consultant for Shift Pharmaceuticals, Overland Park, KS, USA. CL Lorson is the co-founder and CSO of Shift Pharmaceuticals, Overland Park, KS, USA that has licensed SSYA10-001. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was funded by the University of Missouri (Bond Life Sciences Center, Early Concept Grant) and Swedish Research Council grant (DNR 2020-05836).