Potent norovirus inhibitors based on the acyclic sulfamide scaffold

Dou, Dengfeng; Tiew, Kok-Chuan; Mandadapu, Sivakoteswara Rao; Gunnam, Mallikarjuna Reddy; Alliston, Kevin R.; Kim, Yun-Jeong; Chang, Kyeong‐Ok; Groutas, William C.

doi:10.1016/j.bmc.2012.01.030

Cited by 16 publications

(11 citation statements)

References 15 publications

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“…15–16 Cleavage is at the P 1 -P 1 ’ (Q–G) scissile bond. We have recently reported an array of norovirus inhibitors, including acyclic and cyclic sulfamide 17–19 and piperazine 20 derivatives. We have also disclosed for the first time peptidyl transition state (TS) inhibitors, 13a–e TS mimics, 13f as well as macrocyclic inhibitors 13g effective in enzyme and cell based assays.…”

Section: Introductionmentioning

confidence: 99%

Structure-Guided Design and Optimization of Dipeptidyl Inhibitors of Norovirus 3CL Protease. Structure–Activity Relationships and Biochemical, X-ray Crystallographic, Cell-Based, and In Vivo Studies

et al. 2015

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Norovirus infection constitutes the primary cause of acute viral gastroenteritis. There are currently no vaccines or norovirus-specific antiviral therapeutics available for the management of norovirus infection. Norovirus 3C-like protease is essential for viral replication, consequently, inhibition of this enzyme is a fruitful avenue of investigation that may lead to the emergence of anti-norovirus therapeutics. We describe herein the optimization of dipeptidyl inhibitors of norovirus 3C-like protease using iterative SAR, X-ray crystallographic, and enzyme and cell-based studies. We also demonstrate herein in vivo efficacy of an inhibitor using the murine model of norovirus infection.

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Section: Introductionmentioning

confidence: 99%

Structure-Guided Design and Optimization of Dipeptidyl Inhibitors of Norovirus 3CL Protease. Structure–Activity Relationships and Biochemical, X-ray Crystallographic, Cell-Based, and In Vivo Studies

et al. 2015

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“…5 There are currently no effective vaccines or antiviral agents for combating norovirus infection; consequently, there is an urgent need for the discovery of small molecule therapeutics for the management and treatment of norovirus infection. 6–7 Recently-reported small molecule norovirus inhibitors include cyclic and acyclic sulfamide derivatives, 8–10 piperazine derivatives, 11 pyranobenzopyrones, 12 nitazoxanide, 13 and other chemotypes. 14 …”

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confidence: 99%

Inhibition of norovirus 3CL protease by bisulfite adducts of transition state inhibitors

Mandadapu

Gunnam

Tiew

et al. 2013

Bioorganic & Medicinal Chemistry Letters

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Noroviruses are the most common cause of acute viral gastroenteritis, accounting for >21 million cases annually in the U.S. alone. Norovirus infections constitute an important health problem for which there are no specific antiviral therapeutics or vaccines. In this study, a series of bisulfite adducts derived from representative transition state inhibitors (dipeptidyl aldehydes and α-ketoamides) was synthesized and shown to exhibit anti-norovirus activity in a cell-based replicon system. The ED50 of the most effective inhibitor was 60 nM. This study demonstrates for the first time the utilization of bisulfite adducts of transition state inhibitors in the inhibition of norovirus 3C-like protease in vitro and in a cell-based replicon system. The approach described herein can be extended to the synthesis of the bisulfite adducts of other classes of transition state inhibitors of serine and cysteine proteases, such as α-ketoheterocycles and α-ketoesters.

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“…These include cyclic and acyclic sulfamides [90–91] and structural variants [92–94], pyranobenzopyrones [95], and chromones [96] (Figure 9). …”

Section: Drugs Against Known Targetsmentioning

confidence: 99%

Anti-norovirus therapeutics: a patent review (2010-2015)

Kankanamalage

Weerawarna

Kim

et al. 2016

Expert Opinion on Therapeutic Patents

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Introduction Human noroviruses are the primary causative agents of acute gastroenteritis and are a pressing public health burden worldwide. There are currently no vaccines or small molecule therapeutics available for the treatment or prophylaxis of norovirus infections. An improved understanding of norovirus biology, as well as the pathogenic mechanisms underlying the disease, has provided the impetus for a range of intense exploratory drug discovery efforts targeting viral and host factors. Areas covered An overview of norovirus inhibitors disclosed in the patent literature (2010-present) and Clinicaltrials.gov is presented. The review is further enriched and supplemented by recent literature reports. Expert opinion Seminal discoveries made in recent years, including a better understanding of the pathobiology and life cycle of norovirus, the identification and targeting of multiple viral and host factors, the advent of a replicon system and a small animal model for the preclinical evaluation of lead compounds, and the availability of high resolution X-ray crystal structures that can be utilized in structure-based drug design and lead optimization campaigns, collectively suggest that a small molecule therapeutic and prophylactic for norovirus infection is likely to emerge in the not too distant future.

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Potent norovirus inhibitors based on the acyclic sulfamide scaffold

Cited by 16 publications

References 15 publications

Structure-Guided Design and Optimization of Dipeptidyl Inhibitors of Norovirus 3CL Protease. Structure–Activity Relationships and Biochemical, X-ray Crystallographic, Cell-Based, and In Vivo Studies

Structure-Guided Design and Optimization of Dipeptidyl Inhibitors of Norovirus 3CL Protease. Structure–Activity Relationships and Biochemical, X-ray Crystallographic, Cell-Based, and In Vivo Studies

Inhibition of norovirus 3CL protease by bisulfite adducts of transition state inhibitors

Anti-norovirus therapeutics: a patent review (2010-2015)

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