Potent inhibition of Norwalk virus by cyclic sulfamide derivatives

Dou, Dengfeng; Tiew, Kok-Chuan; He, Guijia; Mandadapu, Sivakoteswara Rao; Aravapalli, Sridhar; Alliston, Kevin R.; Kim, Yun-Jeong; Chang, Kyeong‐Ok; Groutas, William C.

doi:10.1016/j.bmc.2011.08.054

Cited by 26 publications

(24 citation statements)

References 16 publications

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“…In the case of inhibitors incorporating an aldehyde or α-ketoamide functionality in their structure, interaction with the active site cysteine (Cys139) leads to the formation of a reversible adduct (Figure 2). 17a–c …”

Section: Resultsmentioning

confidence: 99%

“…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%

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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: Resultsmentioning

confidence: 99%

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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“…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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“…We have recently reported that cyclosulfamide-based derivatives potently inhibit norovirus replication in a cell-based system [4] and have, furthermore, used a scaffold hopping strategy to identify additional classes of compounds that inhibit noroviruses [5]. The multiple points of diversity present in structure (I) (Figure 1) were used to carry out structural modifications to prospect the entire structure and to obtain preliminary validation for advancing this series of compounds into the lead optimization phase [6].…”

Section: Introductionmentioning

confidence: 99%

Cyclosulfamide-based derivatives as inhibitors of noroviruses

Dou

Mandadapu

Alliston

et al. 2012

European Journal of Medicinal Chemistry

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An optimization campaign focused on improving pharmacological activity and physicochemical properties of a recently-identified class of cyclosulfamide-based norovirus inhibitors has been carried out. Dimeric compound 4 was found to be a ~ 10-fold more potent norovirus inhibitor (ED50 0.4 μM) compared to the original hit, however, isonipecotic acid ester derivatives 7e and 10a were shown to have superior therapeutic indices.

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Potent inhibition of Norwalk virus by cyclic sulfamide derivatives

Cited by 26 publications

References 16 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

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

Cyclosulfamide-based derivatives as inhibitors of noroviruses

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