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

Kankanamalage, Anushka C. Galasiti; Kim, Yun-Jeong; Weerawarna, Pathum M.; Uy, Roxanne Adeline Z.; Damalanka, Vishnu C.; Mandadapu, Sivakoteswara Rao; Alliston, Kevin R.; Mehzabeen, N.; Battaile, Kevin P.; Lovell, Scott; Chang, Kyung-Ro; Groutas, William C.

doi:10.1021/jm5019934

Cited by 49 publications

(133 citation statements)

References 58 publications

(92 reference statements)

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“…In addition to potentially higher stability to metabolic enzymes these inhibitors exhibit increased cellular permeability. Further studies should be anticipated that are directed at optimizing the design strategies and improving the pharmacokinetic properties and metabolic stability of HuNoV protease inhibitors using structural analysis and cell-based assays [74–76]. Considering that the active-site residues are highly conserved between the HuNoV proteases in various genogroups and picornavirus proteases, there is a distinct possibility of designing broad-spectrum protease inhibitors as antivirals [77].…”

Section: Non-structural Proteins As Targetsmentioning

confidence: 99%

Antiviral targets of human noroviruses

Prasad

Shanker

Muhaxhiri

et al. 2016

Current Opinion in Virology

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Human noroviruses are major causative agents of sporadic and epidemic gastroenteritis both in children and adults. Currently there are no licensed therapeutic intervention measures either in terms of vaccines or drugs available for these highly contagious human pathogens. Genetic and antigenic diversity of these viruses, rapid emergence of new strains, and their ability to infect a broad population by using polymorphic histo-blood group antigens for cell attachment, pose significant challenges for the development of effective antiviral agents. Despite these impediments, there is progress in the design and development of therapeutic agents. These include capsid-based candidate vaccines, and potential antivirals either in the form of glycomimetics or designer antibodies that block HBGA binding, as well as those that target essential non-structural proteins such as the viral protease and RNA-dependent RNA polymerase. In addition to these classical approaches, recent studies suggest the possibility of interferons and targeting host cell factors as viable approaches to counter norovirus infection. This review provides a brief overview of this progress.

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Section: Non-structural Proteins As Targetsmentioning

confidence: 99%

Antiviral targets of human noroviruses

Prasad

Shanker

Muhaxhiri

et al. 2016

Current Opinion in Virology

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“…Cocrystal structures of NV 3CLpro with peptidyl inhibitors reveal a network of backbone hydrogen bonds involving Ala158, Ala160, Gln110 and His30, as well as two critical hydrogen bonds between His157 and Thr134 and the carbonyl oxygen of the P 1 Gln side chain [27,29,33]. The backbone hydrogen bonds mimic an antiparallel β-sheet and serve to correctly orient and position the inhibitor to the active site [34–35].…”

Section: Resultsmentioning

confidence: 99%

“…The inhibitory activity of the synthesized compounds against NV 3CLpro and their anti-norovirus activity in a cell-based replicon system, were evaluated as described in the experimental section [33,47]. The determined IC 50 in enzyme assay, EC 50 against NV in the replicon harboring cells (HG23 cells) or murine norovirus (MNV) in RAW264.7 cells, and CC 50 values in HG23 cells are listed in Tables 1 and they are the average of at least two determinations.…”

Section: Resultsmentioning

confidence: 99%

Design, synthesis, and evaluation of a novel series of macrocyclic inhibitors of norovirus 3CL protease

Damalanka

Kim

Kankanamalage

et al. 2017

European Journal of Medicinal Chemistry

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Norovirus infections have a major impact on public health worldwide, yet there is a current dearth of norovirus-specific therapeutics and prophylactics. This report describes the discovery of a novel class of macrocyclic inhibitors of norovirus 3C-like protease, a cysteine protease that is essential for virus replication. SAR, structural, and biochemical studies were carried out to ascertain the effect of structure on pharmacological activity and permeability. Insights gained from these studies have laid a solid foundation for capitalizing on the therapeutic potential of the series of inhibitors described herein.

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“…Using a robust FRET-based assay [53] and a cell-based replicon system [18], an array of inhibitors of the protease displaying anti-norovirus activity have been reported, including peptidyl transition (TS) inhibitors (aldehydes, α-ketoamides, α-ketoheterocycles) [54–58] or latent TS inhibitors [59], and TS mimics (α-hydroxyphosphonates) ( vide infra ) [60]. The availability of several high resolution X-ray crystal structures with bound ligands has been invaluable in using structure-guided approaches in the design of inhibitors of the enzyme [55,57,61–65]. …”

Section: Drugs Against Known Targetsmentioning

confidence: 99%

“…Peptidyl inhibitors of 3CL pro have demonstrated efficacy in the murine model of norovirus infection and are currently in preclinical development [55]. The synthesis of peptidyl derivatives of general structure (I) (Figure 2A) can be readily accomplished as illustrated in Figure 2B and representative results are summarized in Tables 1–2.…”

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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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

Cited by 49 publications

References 58 publications

Antiviral targets of human noroviruses

Antiviral targets of human noroviruses

Design, synthesis, and evaluation of a novel series of macrocyclic inhibitors of norovirus 3CL protease

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

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