Oral administration of S-217622, a SARS-CoV-2 main protease inhibitor, decreases viral load and accelerates recovery from clinical aspects of COVID-19

Sasaki, Michihito; Tabata, Koshiro; Kishimoto, Mai; Itakura, Yukari; Kobayashi, Hiroko; Ariizumi, Takuma; Uemura, Kentaro; Toba, Shinsuke; Kusakabe, Shinji; Maruyama, Yuki; Iida, Shun; Nakajima, N.; Suzuki, Tadaki; Yoshida, Saki; Nobori, Haruaki; Sanaki, Takao; Kato, Takamasa; Shishido, Toetsu; Hall, William W.; Orba, Yasuko; Sato, Akihiko; Sawa, Hirofumi

doi:10.1101/2022.02.14.480338

Cited by 12 publications

(19 citation statements)

References 36 publications

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“…Interestingly, Omicron is significantly more susceptible to RDV and GS-441524, although the reasons for this are not understood, as there are no substitutions in Nsp12 that would predict increased potency. This is in line with several other SARS-CoV-2 inhibitors targeting the SARS-CoV-2 RdRp or main protease with different mechanisms of action, which also exhibit increased potency against Omicron compared to ancestral strains ( 40 – 42 ).…”

Section: Discussionsupporting

confidence: 85%

Remdesivir and GS-441524 Retain Antiviral Activity against Delta, Omicron, and Other Emergent SARS-CoV-2 Variants

Pitts

Perry

et al. 2022

Antimicrob Agents Chemother

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Genetic variation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in the emergence and rapid spread of multiple variants throughout the pandemic, of which Omicron is currently the predominant variant circulating worldwide. SARS-CoV-2 variants of concern/variants of interest (VOC/VOI) have evidence of increased viral transmission, disease severity, or decreased effectiveness of vaccines and neutralizing antibodies.

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Section: Discussionsupporting

confidence: 85%

Remdesivir and GS-441524 Retain Antiviral Activity against Delta, Omicron, and Other Emergent SARS-CoV-2 Variants

Pitts

Perry

et al. 2022

Antimicrob Agents Chemother

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“…Nirmatrelvir protects Syrian Golden hamsters from intranasal infection with different VoCs and prevents transmission to untreated co-housed sentinels [7, 8]. Other clinical candidate 3CLpro inhibitors include ensitrelvir (S-217622), a non-peptidic, non-covalent SARS-CoV-2 3CLpro inhibitor [9, 10], and PBI-0451 [11]. The clinical development of lufotrelvir, an intravenous pro-drug of PF-00835321 has been discontinued [12, 13].…”

Section: Introductionmentioning

confidence: 99%

The substitutions L50F, E166A and L167F in SARS-CoV-2 3CLpro are selected by a protease inhibitorin vitroand confer resistance to nirmatrelvir

Jochmans

Liu²,

Donckers

et al. 2022

Preprint

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The SARS-CoV-2 main protease (3CLpro) has an indispensable role in the viral life cycle and is a therapeutic target for the treatment of COVID-19. The potential of 3CLpro-inhibitors to select for drug-resistant variants needs to be established. Therefore SARS-CoV-2 was passaged in vitro in the presence of increasing concentrations of ALG-097161, a probe compound designed in the context of a 3CLpro drug discovery program. We identified a combination of amino acid substitutions in 3CLpro (L50F E166A L167F) that is associated with > 20x increase in EC50 values for ALG-097161, nirmatrelvir (PF-07321332) and PF-00835231. While two of the single substitutions (E166A and L167F) provide low-level resistance to the inhibitors in a biochemical assay, the triple mutant results in the highest levels of resistance (6- to 72-fold). All substitutions are associated with a significant loss of enzymatic 3CLpro activity, suggesting a reduction in viral fitness. Structural biology analysis indicates that the different substitutions reduce the number of inhibitor/enzyme interactions while the binding of the substrate is maintained. These observations will be important for the interpretation of resistance development to 3CLpro inhibitors in the clinical setting.

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“…The consortium is hoping to advance this compound or an analog to clinical development. Shionogi has reported on S-217622 ( 5 ), an orally delivered Mpro inhibitor with activity against SARS-CoV-2 variants (EC 50 = 23.9–61.7 nM, 293T-ACE2-TMPRSS2 cells), that has completed Phase 2a studies [ 81 , 82 ].…”

Section: Main Protease (Mpro)mentioning

confidence: 99%

Antiviral Drug Discovery for the Treatment of COVID-19 Infections

Correia

Seagal

et al. 2022

Viruses

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The coronavirus disease 2019 (COVID-19) pandemic is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a recently emerged human coronavirus. COVID-19 vaccines have proven to be successful in protecting the vaccinated from infection, reducing the severity of disease, and deterring the transmission of infection. However, COVID-19 vaccination faces many challenges, such as the decline in vaccine-induced immunity over time, and the decrease in potency against some SARS-CoV-2 variants including the recently emerged Omicron variant, resulting in breakthrough infections. The challenges that COVID-19 vaccination is facing highlight the importance of the discovery of antivirals to serve as another means to tackle the pandemic. To date, neutralizing antibodies that block viral entry by targeting the viral spike protein make up the largest class of antivirals that has received US FDA emergency use authorization (EUA) for COVID-19 treatment. In addition to the spike protein, other key targets for the discovery of direct-acting antivirals include viral enzymes that are essential for SARS-CoV-2 replication, such as RNA-dependent RNA polymerase and proteases, as judged by US FDA approval for remdesivir, and EUA for Paxlovid (nirmatrelvir + ritonavir) for treating COVID-19 infections. This review presents an overview of the current status and future direction of antiviral drug discovery for treating SARS-CoV-2 infections, covering important antiviral targets such as the viral spike protein, non-structural protein (nsp) 3 papain-like protease, nsp5 main protease, and the nsp12/nsp7/nsp8 RNA-dependent RNA polymerase complex.

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Oral administration of S-217622, a SARS-CoV-2 main protease inhibitor, decreases viral load and accelerates recovery from clinical aspects of COVID-19

Cited by 12 publications

References 36 publications

Remdesivir and GS-441524 Retain Antiviral Activity against Delta, Omicron, and Other Emergent SARS-CoV-2 Variants

Remdesivir and GS-441524 Retain Antiviral Activity against Delta, Omicron, and Other Emergent SARS-CoV-2 Variants

The substitutions L50F, E166A and L167F in SARS-CoV-2 3CLpro are selected by a protease inhibitorin vitroand confer resistance to nirmatrelvir

Antiviral Drug Discovery for the Treatment of COVID-19 Infections

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