key: cord-0823709-qjpb51gm
authors: Habtemariam, Solomon; Nabavi, Seyed fazel; Banach, Maciej; Berindan-Neagoe, Ioana; kasturi Sarkar,; Sil, Parames C.; Nabavi, Seyed Mohammad
title: Should we try SARS-CoV-2 Helicase Inhibitors for COVID-19 Therapy?
date: 2020-05-31
journal: Arch Med Res
DOI: 10.1016/j.arcmed.2020.05.024
sha: 859bb72b4ce4c917bfeb51f3ca693dc5b2dbaa31
doc_id: 823709
cord_uid: qjpb51gm

The discovery of new drugs for treating the new coronavirus (SARS-CoV-2) or repurposing those already in use for other viral infections is possible through understanding of the viral replication cycle and pathogenicity. This article highlights the advantage of targeting one of the non-structural proteins, helicase (nsp13), over other SARS-CoV-2 proteins. Highlighting the experience gained from targeting Nsp13 in similar coronaviruses (SARS-CoV and MERS) and known inhibitors, the article calls for research on helicase inhibitors as potential COVID-19 therapy.

OPINION Should we try SARS-CoV-2 Helicase Inhibitors for COVID-19 Therapy?

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral pandemic that causes coronavirus disease 2019 (COVID-19) is the worst respiratory disease outbreak of the generation, if not a century, and currently crippling the entire global fabric of the human socioeconomic life. As with other coronaviruses, SARS-CoV-2 is believed to jump species barriers and the first known human infection appeared in the Wuhan province of China in December 2019. With no known efficacious therapy for COVID-19, repurposing other known antiviral drugs and pathologies related to the lethal episode of COVID-19 are our best approach for rigorous experimental (in vitro and in vivo) tests and clinical trials. In this regard, the closely related coronaviruses such as severe acute respiratory syndrome (SARS-CoV) and Middle East respiratory syndrome (MERS-CoV) gave us good level of understanding in the replication cycle of the virus; the host reaction to infection leading to pneumonia and organ failure (or death); and potential therapeutic targets ( Figure 1 ). The close genomic relationship of SARS-CoV-2 with SARS-CoV, for example, with 80% nucleotide identity has been a good playground for putting forward similar therapeutic insights. Although their infectivity was not as severe as the above-mentioned three coronaviruses, other human coronavirus that gave us clue on potential coronavirus therapeutics are 229E, HKU1, NL63 and OC43. One of the most attractive therapeutic approaches that we learnt from these coronaviruses is based on targeting key enzymes such as proteases, polymerases, and helicases, which are all involved in the replication Taking all these data together, it is now apparent that inhibitors of the nsp13 activity offer potential therapeutic option for coronavirus including SAR-CoV-2. Among the various approaches of nsp13 activity inhibition are targeting ATP binding or direct NTPase activity, nucleic acids binding to the helicase, blocking helicase translocation, etc. The class of compounds identified with a promise through such mechanisms include benzotriazole, imidazole, imidazodiazepine, phenothiazine, quinoline, anthracycline, triphenylmethane, tropolone, pyrrole, acridone, small peptide, and bananin derivatives (8). For example, bananins have been shown to inhibit SARS-CoV ATPase activity leading to inhibition of viral replication in vitro with IC50 values far less than 10 mM (9). On these bases, studies on the potential of viral helicase inhibitors in SARS-CoV-2 infection or COVID-19 is well justified.

Lipid lowering therapy and Renin-Angiotensin-Aldosterone System Inhibitors in the era of the COVID-19 pandemic

Structure and mechanism of helicases and nucleic acid translocases

Delicate structural coordination of the Severe Acute Respiratory Syndrome coronavirus Nsp13 upon ATP hydrolysis

Structural elucidation of SARS-CoV-2 vital proteins: computational methods reveal potential drug candidates against Main protease, Nsp12 RNA-dependent RNA polymerase and Nsp13 helicase

Mechanism of nucleic acid unwinding by SARS-CoV helicase

A high ATP concentration enhances the cooperative translocation of the SARS coronavirus helicase nsP13 in the unwinding of duplex

Design, synthesis and molecular docking of novel triazole derivatives as potential CoV helicase inhibitors

Inhibition of RNA helicases of ssRNA+ virus belonging to

Coronaviridae and Picornaviridae families

The adamantane-derived bananins are potent inhibitors of the helicase activities and replication of SARS coronavirus

All authors have declared no conflict on interest in the writing of this manuscript.