Discovery of S-217622, a Non-Covalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19

  title={Discovery of S-217622, a Non-Covalent Oral SARS-CoV-2 3CL Protease Inhibitor Clinical Candidate for Treating COVID-19},
  author={Yuto Unoh and Shotaro Uehara and Kenji S. Nakahara and Haruaki Nobori and Yukiko Yamatsu and Shiho Yamamoto and Yuki Maruyama and Yoshiyuki Taoda and Koji Kasamatsu and Takahiro Suto and Kensuke Kouki and Atsufumi Nakahashi and Shotaro Kawashima and Takao Sanaki and Shinsuke Toba and Kentaro Uemura and Tohru Mizutare and Shigeru Ando and Michihito Sasaki and Yasuko Orba and Hirofumi Sawa and Akihiko Sato and Takafumi Sato and Teruhisa Kato and Yuki Tachibana},
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and threatens public health and safety. Despite the rapid global spread of COVID-19 vaccines, effective oral antiviral drugs are urgently needed. Here, we describe the discovery of S-217622, the first oral non-covalent, non-peptidic SARS-CoV-2 3CL protease inhibitor clinical candidate. S-217622 was discovered via virtual screening followed… 

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

This study provides evidence that S-217622, an antiviral agent that is under evaluation in a phase II/III clinical trial, possesses remarkable antiviral potency and efficacy against SARS-CoV-2 and is a prospective oral therapeutic option for COVID-19.

Fluorine in Medicinal Chemistry: In Perspective to COVID-19

An update on fluorinated anti-COVID-19 drugs is given by providing the key information and current knowledge of these drugs, including their molecular design, metabolism and pharmacokinetics, and mechanism of action.

Structural basis of nirmatrelvir and ensitrelvir resistance profiles against SARS-CoV-2 Main Protease naturally occurring polymorphisms

Describing naturally occurring polymorphisms that are already in circulation and within the radius of action of nirmatrelvir and ensitrelvir will assist the monitoring of potential resistant strains, support the design of combined therapy to avoid resistance, and assist the development of a next generation of Mpro inhibitors.

Characterization and antiviral susceptibility of SARS-CoV-2 Omicron/BA.2

Findings suggest that the replication and pathogenicity of BA.2 is comparable to that ofBA.1 in rodents and that several therapeutic monoclonal antibodies and antiviral compounds are effective against Omicron/BA.2 variants.

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

This work describes for the first time a pathway that allows SARS-CoV-2 to develop resistance against Paxlovid in vitro, and identifies a combination of amino acid substitutions in 3CLpro that is associated with > 20x increase in EC50 values for ALG-097161, nirmatrelvir and PF-00835231.

Accelerating Inhibitor Discovery for Multiple SARS-CoV-2 Targets with a Single, Sequence-Guided Deep Generative Framework

The broad utility of a single deep generative framework toward discovering novel drug-like inhibitor molecules against two distinct SARS-CoV-2 targets — the main protease and the receptor binding domain (RBD) of the spike protein are demonstrated.

A Randomized Phase 2/3 Study of Ensitrelvir, a Novel Oral SARS-CoV-2 3C-Like Protease Inhibitor, in Japanese Patients with Mild-to-Moderate COVID-19 or Asymptomatic SARS-CoV-2 Infection: Results of the Phase 2a Part

Ensitrelvir treatment demonstrated rapid SARS-CoV-2 clearance and was well tolerated (Japan Registry of Clinical Trials identifier: jRCT2031210350).



Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors

A programme of structure-assisted drug design and high-throughput screening identifies six compounds that inhibit the main protease of SARS-CoV-2, demonstrating the ability of this strategy to isolate drug leads with clinical potential.

An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19

The discovery and characterization of a drug against the main protease involved in the cleavage of polyproteins involved in viral replication is reported, which can be administered orally, has good selectivity and safety profiles, and protects against infection in a mouse model.

Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors

The pharmacokinetic characterization of the optimized inhibitor reveals a pronounced lung tropism and suitability for administration by the inhalative route and work that may provide a basis for development of anticoronaviral drugs.

Structure-Based Optimization of ML300-Derived, Noncovalent Inhibitors Targeting the Severe Acute Respiratory Syndrome Coronavirus 3CL Protease (SARS-CoV-2 3CLpro)

In vitro DMPK profiling highlights key areas where further optimization in the series is required to obtain useful in vivo probes, and nanomolar activity in these respective assays, comparable in potency to remdesivir, have implications for antiviral development to combat current and future SARS-like zoonotic coronavirus outbreaks.

Open Science Discovery of Oral Non-Covalent SARS-CoV-2 Main Protease Inhibitor Therapeutics

The COVID Moonshot, a fully open-science structure-enabled drug discovery campaign targeting the SARS-CoV-2 main protease, discovered a novel chemical scaffold that is differentiated from current clinical candidates in terms of toxicity, resistance, and pharmacokinetics liabilities, and developed it into noncovalent orally-bioavailable nanomolar inhibitors with clinical potential.

Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease

A large-scale screen of electrophile and non-covalent fragments is performed through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication.

The SARS-CoV-2 main protease as drug target

Postinfection treatment with a protease inhibitor increases survival of mice with a fatal SARS-CoV-2 infection

The results suggest that deuterated variants of a coronavirus protease inhibitor, GC376, have excellent potential as antiviral agents against SARS-CoV-2.

Potent SARS-CoV-2 Direct-Acting Antivirals Provide an Important Complement to COVID-19 Vaccines

Unlike the Spanish Flu era, this time research groups from around the world have developed a myriad of vaccines that illicit antibody and T-cell immunity, no doubt accelerated by research accomplished after the SARS-CoV-1 outbreak in 2002−2003 and the Middle Eastern Respiratory Syndrome outbreak in 2008.

Potency, Safety, and Pharmacokinetic Profiles of Potential Inhibitors Targeting SARS-CoV-2 Main Protease

The potency, safety, and pharmacokinetic profiles of potential inhibitors of SARS-CoV-2 Mpro are discussed and forward directions on the development of future studies focusing on COVID-19 therapeutics are forward directions.