Quest for a COVID-19 Cure by Repurposing Small-Molecule Drugs: Mechanism of Action, Clinical Development, Synthesis at Scale, and Outlook for Supply

Savi, Chris De; Hughes, David L.; Kværnø, Lisbet

doi:10.1021/acs.oprd.0c00233

Cited by 84 publications

(91 citation statements)

References 93 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Camostat (also called FOY-305) is a trypsin-like serine protease inhibitor approved in Japan (as the mesylate salt) for the treatment of pancreatitis and reflux esophagitis 18 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

An Enzymatic TMPRSS2 Assay for Assessment of Clinical Candidates and Discovery of Inhibitors as Potential Treatment of COVID-19

Shrimp

Kales

Sanderson

et al. 2020

Preprint

View full text Add to dashboard Cite

SARS-CoV-2 is the viral pathogen causing the COVID19 global pandemic.Consequently, much research has gone into the development of pre-clinical assays for the discovery of new or repurposing of FDA-approved therapies. Preventing viral entry into a host cell would be an effective antiviral strategy. One mechanism for SARS-CoV-2 entry occurs when the spike protein on the surface of SARS-CoV-2 binds to an ACE2 receptor followed by cleavage at two cut sites ("priming") that causes a conformational change allowing for viral and host membrane fusion. This fusion event is proceeded by release of viral RNA within the host cell. TMPRSS2 has an extracellular protease domain capable of cleaving the spike protein to initiate membrane fusion. Additionally, knock-out studies in mice have demonstrated reduced infection in the absence of TMPRSS2 with no detectable physiological impact; thus, TMPRSS2 is an attractive target for therapeutic development. A validated inhibitor of TMPRSS2 protease activity would be a valuable tool for studying the impact TMPRSS2 has in viral entry and potentially be an effective antiviral therapeutic. To enable inhibitor discovery and profiling of FDA-approved therapeutics, we describe an assay for the biochemical screening of recombinant TMPRSS2 suitable for high throughput application. We demonstrate effectiveness to quantify inhibition down to subnanomolar concentrations by assessing the inhibition of camostat, nafamostat and gabexate, clinically approved agents in Japan for pancreatitis due to their inhibition of trypsin-like proteases.Nafamostat and camostat are currently in clinical trials against COVID19. The rank order potency for the three inhibitors is: nafamostat (IC50 = 0.27 nM), camostat (IC50 = 6.2 nM) and gabexate (IC50 = 130 nM). Further profiling of these three inhibitors against a panel of proteases provides insight into selectivity and potency.

show abstract

“…Camostat (also called FOY-305) is a trypsin-like serine protease inhibitor approved in Japan (as the mesylate salt) for the treatment of pancreatitis and reflux esophagitis 18 .…”

Section: Introductionmentioning

confidence: 99%

“…At least eight clinical trials for treating patients are currently underway 19 . It was developed by Ono Pharmaceuticals (Japan, patented in 1977 18,20 ).…”

Section: Introductionmentioning

confidence: 99%

An Enzymatic TMPRSS2 Assay for Assessment of Clinical Candidates and Discovery of Inhibitors as Potential Treatment of COVID-19

Shrimp

Kales

Sanderson

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Under such circumstances, several existing antiviral drugs and drug candidates are actively evaluated for their therapeutic potential for this disease. 6 − 8 Among them, remdesivir (GS-5734, 1 ; Figure 1 ) represents one of the most promising compounds. 8 − 10 …”

Section: Introductionmentioning

confidence: 99%

Improvement of the C-glycosylation Step for the Synthesis of Remdesivir

Xue

Zhou²,

Zhou

et al. 2020

Org. Process Res. Dev.

View full text Add to dashboard Cite

The bulk supply of the antiviral C -nucleoside analogue remdesivir is largely hampered by a low-yielding C -glycosylation step in which the base is coupled to the pentose unit. Here, we disclose a significantly improved methodology for this critical transformation. By utilizing diisopropylamine as a cost-effective additive, the addition reaction furnishes an optimal yield of 75% of the desired ribofuranoside adduct, representing the highest yield obtained thus far for this key step. The method proved suitable for hectogram scale synthesis without column chromatographic operations.

show abstract

“…However, while there was imperceptible evidence that camostat and relavant compounds inhibit SARS-CoV-2 mediated TMPRSS2 cell entry; there was no significant biochemical evidence in the literature. Ono Pharmaceuticals produced Camostat 9 . A clinical investigation of camostat mesilate was applied against non-alcoholic, intermediate pancreatic dyspepsia infection, which exhibited just minor, but no significant adverse effects 8 .…”

Section: Resultsmentioning

confidence: 99%

Repurposable Drug Candidates are Potential Therapeutic Target against Global SARS-CoV-2 Crisis

Rahman

Mina

Das

et al. 2020

J. Drug Delivery Ther.

View full text Add to dashboard Cite

This review provides a pharmacological approach to combat Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2) based on two comprehensive denominations which could be specifically intended for viral replication process by either inhibiting essential genomic viral enzymes or preventing viral entry to human cells. These denominations focused on immune therapies either to improve innate antiviral immune responses or to reduce impairment triggered by underactive inflammatory reactions. A variety of drug candidates are available which can inhibit SARS-CoV-2 infection and replication, comprising serine protease inhibitors: Transmembrane Orotease/Serine Subfamily member 2 (TMPRSS2), camostat mesylate, nafamostat mesylate, and angiotensin-converting enzyme inhibitors. This review is also concerned with identifying drugs and ongoing clinical trials with their mechanisms of action against SARS-CoV-2. Chloroquine and hydroxychloroquine, monoclonal antibody, off-label antiviral drugs, nucleotide analog remdesivir and broad-spectrum antiviral drugs also could be used as inhibitors of SARS-CoV-2. Moreover, non-steroidal anti-inflammatory drugs (NSAIDs), dexamethasone, and antiviral phytochemicals that are currently reachable, can prevent SARS-CoV-2 pandemic morbidity and mortality. Keywords: COVID-19; Antiviral drugs; NSAIDs; ACE2; Clinical trials

show abstract

Quest for a COVID-19 Cure by Repurposing Small-Molecule Drugs: Mechanism of Action, Clinical Development, Synthesis at Scale, and Outlook for Supply

Cited by 84 publications

References 93 publications

An Enzymatic TMPRSS2 Assay for Assessment of Clinical Candidates and Discovery of Inhibitors as Potential Treatment of COVID-19

An Enzymatic TMPRSS2 Assay for Assessment of Clinical Candidates and Discovery of Inhibitors as Potential Treatment of COVID-19

Improvement of the C-glycosylation Step for the Synthesis of Remdesivir

Repurposable Drug Candidates are Potential Therapeutic Target against Global SARS-CoV-2 Crisis

Contact Info

Product

Resources

About