Therapeutic potential of compounds targeting SARS-CoV-2 helicase

Halma, Matthew; Wever, Mark J. A.; Abeln, Sanne; Roche, Didier M.; Wuite, Gijs J.L.

doi:10.3389/fchem.2022.1062352

Cited by 5 publications

(3 citation statements)

References 111 publications

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“… 23 The published SARS-CoV Nsp13 helicase activity inhibitor, SSYA10-001, also inhibited SARS-CoV-2 Nsp13 ( Figure 2 D), which further validated the experimental setup. 17 , 31 − 33 IOWH-032 and TEL were titrated into duplex-DNA reactions initiated with excess ATP with and without detergent to assess the possible effects of compound aggregation ( Figures 2 E,F and Figures S5C,D ). Both compounds disrupted Nsp13 helicase activity at micromolar concentrations regardless of the presence of detergent, which indicated that inhibition resulted from each compound binding to enzyme, and not aggregate formation.…”

Section: Resultsmentioning

confidence: 99%

A Repurposed Drug Interferes with Nucleic Acid to Inhibit the Dual Activities of Coronavirus Nsp13

Soper,

Yardumian,

Chen

et al. 2024

ACS Chem. Biol.

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The recent pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlighted a critical need to discover more effective antivirals. While therapeutics for SARS-CoV-2 exist, its nonstructural protein 13 (Nsp13) remains a clinically untapped target. Nsp13 is a helicase responsible for unwinding double-stranded RNA during viral replication and is essential for propagation. Like other helicases, Nsp13 has two active sites: a nucleotide binding site that hydrolyzes nucleoside triphosphates (NTPs) and a nucleic acid binding channel that unwinds double-stranded RNA or DNA. Targeting viral helicases with small molecules, as well as the identification of ligand binding pockets, have been ongoing challenges, partly due to the flexible nature of these proteins.Here, we use a virtual screen to identify ligands of Nsp13 from a collection of clinically used drugs. We find that a known ion channel inhibitor, IOWH-032, inhibits the dual ATPase and helicase activities of SARS-CoV-2 Nsp13 at low micromolar concentrations. Kinetic and binding assays, along with computational and mutational analyses, indicate that IOWH-032 interacts with the RNA binding interface, leading to displacement of nucleic acid substrate, but not bound ATP. Evaluation of IOWH-032 with microbial helicases from other superfamilies reveals that it is selective for coronavirus Nsp13. Furthermore, it remains active against mutants representative of observed SARS-CoV-2 variants. Overall, this work provides a new inhibitor for Nsp13 and provides a rationale for a recent observation that IOWH-032 lowers SARS-CoV-2 viral loads in human cells, setting the stage for the discovery of other potent viral helicase modulators.

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Section: Resultsmentioning

confidence: 99%

A Repurposed Drug Interferes with Nucleic Acid to Inhibit the Dual Activities of Coronavirus Nsp13

Soper,

Yardumian,

Chen

et al. 2024

ACS Chem. Biol.

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“…Compounds reported in non-English publications could be skipped in this review. In a recently published review paper, 111 some of the cited references reported a few compounds tested against the SARS-CoV-2 helicase; however, these studies did not appear in our list of articles . This could be attributed to the fact that their titles and abstracts did not fit the inclusion criteria of this current systematic review.…”

Section: Discussionmentioning

confidence: 99%

Coronaviruses SARS-CoV, MERS-CoV, and SARS-CoV-2 helicase inhibitors: a systematic review of in vitro studies

Mehyar

2023

Journal of Virus Eradication

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“…SARS-CoV-2 helicase is a 5′→3′ translocated helicase, which is powered by deoxyribonucleotide triphosphate. It acts on deoxyribonucleic acid substrates, catalyzes the unwinding of double-stranded RNA and then replicates in large quantities, playing a key role in viral genome replication [ 86 , 87 , 88 ].…”

Section: Fluorescence-based Drug Screening Methods For Novel Coronavi...mentioning

confidence: 99%

Development of Fluorescence-Based Assays for Key Viral Proteins in the SARS-CoV-2 Infection Process and Lifecycle

Deng,

Zhang,

Yan

et al. 2024

IJMS

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Since the appearance of SARS-CoV-2 in 2019, the ensuing COVID-19 (Corona Virus Disease 2019) pandemic has posed a significant threat to the global public health system, human health, life, and economic well-being. Researchers worldwide have devoted considerable efforts to curb its spread and development. The latest studies have identified five viral proteins, spike protein (Spike), viral main protease (3CLpro), papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp), and viral helicase (Helicase), which play crucial roles in the invasion of SARS-CoV-2 into the human body and its lifecycle. The development of novel anti-SARS-CoV-2 drugs targeting these five viral proteins holds immense promise. Therefore, the development of efficient, high-throughput screening methodologies specifically designed for these viral proteins is of utmost importance. Currently, a plethora of screening techniques exists, with fluorescence-based assays emerging as predominant contenders. In this review, we elucidate the foundational principles and methodologies underpinning fluorescence-based screening approaches directed at these pivotal viral targets, hoping to guide researchers in the judicious selection and refinement of screening strategies, thereby facilitating the discovery and development of lead compounds for anti-SARS-CoV-2 pharmaceuticals.

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Therapeutic potential of compounds targeting SARS-CoV-2 helicase

Cited by 5 publications

References 111 publications

A Repurposed Drug Interferes with Nucleic Acid to Inhibit the Dual Activities of Coronavirus Nsp13

A Repurposed Drug Interferes with Nucleic Acid to Inhibit the Dual Activities of Coronavirus Nsp13

Coronaviruses SARS-CoV, MERS-CoV, and SARS-CoV-2 helicase inhibitors: a systematic review of in vitro studies

Development of Fluorescence-Based Assays for Key Viral Proteins in the SARS-CoV-2 Infection Process and Lifecycle

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