Structure-Guided Optimization of Dipeptidyl Inhibitors of Norovirus 3CL Protease

Rathnayake, Athri D.; Kim, Yun-Jeong; Dampalla, Chamandi S.; Nguyen, Harry Nhat; Jesri, Abdul-Rahman M.; Kashipathy, M.M.; Lushington, Gerald H.; Battaile, K.P.; Lovell, Scott; Chang, Kyeong‐Ok; Groutas, William C.

doi:10.1021/acs.jmedchem.0c01252

Cited by 14 publications

(24 citation statements)

References 77 publications

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“…Rupintrivir is a protease inhibitor designed for the treatment of human rhinovirus but showed to have broad-spectrum antiviral activity against other picornaviruses, coronaviruses and caliciviruses [ 48 , 128 , 129 , 130 ]. Strategies to improve activity targeting the active site with other scaffolds have been pursued [ 131 ]. Furthermore, other peptidomimetic compounds that interact with the active site of protease have been designed [ 130 ].…”

Section: Antiviral Targets and Known Antiviralsmentioning

confidence: 99%

Current and Future Antiviral Strategies to Tackle Gastrointestinal Viral Infections

et al. 2021

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Acute gastroenteritis caused by virus has a major impact on public health worldwide in terms of morbidity, mortality, and economic burden. The main culprits are rotaviruses, noroviruses, sapoviruses, astroviruses, and enteric adenoviruses. Currently, there are no antiviral drugs available for the prevention or treatment of viral gastroenteritis. Here, we describe the antivirals that were identified as having in vitro and/or in vivo activity against these viruses, originating from in silico design or library screening, natural sources or being repurposed drugs. We also highlight recent advances in model systems available for this (hard to cultivate) group of viruses, such as organoid technologies, and that will facilitate antiviral studies as well as fill some of current knowledge gaps that hamper the development of highly efficient therapies against gastroenteric viruses.

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Section: Antiviral Targets and Known Antiviralsmentioning

confidence: 99%

Current and Future Antiviral Strategies to Tackle Gastrointestinal Viral Infections

et al. 2021

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“…13 ) The 3CL pro enzymes from SARS-CoV and SARS-CoV-2 share nearly 80% sequence identity, 14,15 suggesting that many of the lessons learned for developing SARS therapeutics can be applied to COVID-19. As a note, 3CL pro is not limited to coronaviruses but is also a drug target for the development of antivirals against noroviruses (such as the one involved in gastroenteritis 16 ) or antivirals against enteroviruses (e.g., antiviral drug 3CLpro-1 17 targeting the hand, foot, and mouth disease enterovirus 71 and Rupintrivir -Figure 1-originally developed to fight rhoniviruses 18 ).…”

Section: Vaccines and Therapeuticsmentioning

confidence: 99%

Design, Synthesis and Biological Evaluation of Novel SARS-CoV-2 3CLpro Covalent Inhibitors

Stille¹,

Hennecker²

2021

Preprint

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Severe diseases such as the ongoing COVID-19 pandemic, as well as the previous SARS and MERS outbreaks, are the result of coronavirus infections and have demonstrated the urgent need for antiviral drugs to combat these deadly viruses. Due to its essential role in viral replication and function, 3CLpro> has been identified as a promising target for the development of antiviral drugs. Previously reported SARS-CoV 3CLpro non-covalent inhibitors were used as a starting point for the development of covalent inhibitors of SARS-CoV-2 3CLpro. We report herein our efforts in design and synthesis which led to submicromolar covalent inhibitors when the enzymatic activity of the viral protease was used as a screening platform.

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“…8 ) The 3CL pro enzymes from SARS-CoV and SARS-CoV-2 share nearly 80% identity, 9,10 suggesting that many of the lessons learned for developing SARS therapeutics can be applied to COVID-19. As a note, 3CL pro is not limited to coronaviruses but is also a drug target for the development of antivirals against noroviruses (such as the one involved in gastroenteritis 11 ) or antivirals against enteroviruses (e.g., antiviral drug 3CLpro-1 12 targeting the hand, foot, and mouth disease enterovirus 71 and Rupintrivir originally developed to fight rhoniviruses 13 ).…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Biological Evaluation of Novel SARS-CoV-2 3CLpro Covalent Inhibitors

Stille¹,

Tjutrins²,

Wang³

et al. 2021

Preprint

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Severe diseases such as the ongoing COVID-19 pandemic, as well as the previous SARS and MERS outbreaks, are the result of coronavirus infections and have demonstrated the urgent need for antiviral drugs to combat these deadly viruses. Due to its essential role in viral replication and function, 3CLpro has been identified as a promising target for the development of antiviral drugs. Previously reported SARS-CoV 3CLpro non-covalent inhibitors were used as a starting point for the development of covalent inhibitors of SARS-CoV-2 3CLpro. We report herein our efforts in design and synthesis which led to submicromolar covalent inhibitors when the enzymatic activity of the viral protease was used as a screening platform.

show abstract

Structure-Guided Optimization of Dipeptidyl Inhibitors of Norovirus 3CL Protease

Cited by 14 publications

References 77 publications

Current and Future Antiviral Strategies to Tackle Gastrointestinal Viral Infections

Current and Future Antiviral Strategies to Tackle Gastrointestinal Viral Infections

Design, Synthesis and Biological Evaluation of Novel SARS-CoV-2 3CLpro Covalent Inhibitors

Design, Synthesis and Biological Evaluation of Novel SARS-CoV-2 3CLpro Covalent Inhibitors

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