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

Damalanka, Vishnu C.; Kim, Yun-Jeong; Kankanamalage, Anushka C. Galasiti; Lushington, Gerald H.; Mehzabeen, N.; Battaile, Kevin P.; Lovell, Scott; Chang, Kyung-Ro; Groutas, William C.

doi:10.1016/j.ejmech.2016.12.033

Cited by 12 publications

(17 citation statements)

References 60 publications

(59 reference statements)

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“…This variability observed in the NoV proteases may be a stumbling block in the development of effective cross-reactive inhibitors. Several groups are engaged in developing structure-based NoV protease inhibitors as a potential therapeutic against NoVs (25)(26)(27). However, the inhibitors designed thus far are based on the available NV Pro structures, and although they show potent activity against GI proteases, they are not efficient in inhibiting the GII proteases, for which there is no structural information available (26).…”

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confidence: 99%

GII.4 Norovirus Protease Shows pH-Sensitive Proteolysis with a Unique Arg-His Pairing in the Catalytic Site

Viskovska

Zhao

Shanker

et al. 2019

J Virol

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Human noroviruses (NoVs) are the main cause of epidemic and sporadic gastroenteritis. Phylogenetically, noroviruses are divided into seven genogroups, with each divided into multiple genotypes. NoVs belonging to genogroup II and genotype 4 (GII.4) are globally most prevalent. Genetic diversity among the NoVs and the periodic emergence of novel strains present a challenge for the development of vaccines and antivirals to treat NoV infection. NoV protease is essential for viral replication and is an attractive target for the development of antivirals. The available structure of GI.1 protease provided a basis for the design of inhibitors targeting the active site of the protease. These inhibitors, although potent against the GI proteases, poorly inhibit the GII proteases, for which structural information is lacking. To elucidate the structural basis for this difference in the inhibitor efficiency, we determined the crystal structure of a GII.4 protease. The structure revealed significant changes in the S2 substratebinding pocket, making it noticeably smaller, and in the active site, with the catalytic triad residues showing conformational changes. Furthermore, a conserved arginine is found inserted into the active site, interacting with the catalytic histidine and restricting substrate/inhibitor access to the S2 pocket. This interaction alters the relationships between the catalytic residues and may allow for a pHdependent regulation of protease activity. The changes we observed in the GII.4 protease structure may explain the reduced potency of the GI-specific inhibitors against the GII protease and therefore must be taken into account when designing broadly cross-reactive antivirals against NoVs. IMPORTANCE Human noroviruses (NoVs) cause sporadic and epidemic gastroenteritis worldwide. They are divided into seven genogroups (GI to GVII), with each genogroup further divided into several genotypes. Human NoVs belonging to genogroup II and genotype 4 (GII.4) are the most prevalent. Currently, there are no vaccines or antiviral drugs available for NoV infection. The protease encoded by NoV is considered a valuable target because of its essential role in replication. NoV protease structures have only been determined for the GI genogroup. We show here that the structure of the GII.4 protease exhibits several significant changes from GI proteases, including a unique pairing of an arginine with the catalytic histidine that makes the proteolytic activity of GII.4 protease pH sensitive. A comparative analysis of NoV protease structures may provide a rational framework for structure-based drug design of broadly cross-reactive inhibitors targeting NoVs.

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confidence: 99%

GII.4 Norovirus Protease Shows pH-Sensitive Proteolysis with a Unique Arg-His Pairing in the Catalytic Site

Viskovska

Zhao

Shanker

et al. 2019

J Virol

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“…After refluxing for 14 h, the solvent was removed on the rotary evaporator to yield pure isocyanates 2a-b as colorless oils. 46 Synthesis of compounds 3a-e. General procedure. To a 250 mL round bottom flask kept under nitrogen atmosphere was added a 2.0 M solution (1.40 mL, 2.76 mmol) of the appropriate Grignard reagent in THF and the solution was cooled to 0-5°C.…”

Section: General Synthesis Purification and Analytical Chemistry Prmentioning

confidence: 99%

“…The crude product was purified by column chromatography to yield alcohols 3a-c and 3d-e as oils. 46 Synthesis of carbamates 4a-d and 9a-b. General procedure.…”

Section: General Synthesis Purification and Analytical Chemistry Prmentioning

confidence: 99%

Piperidine carbamate peptidomimetic inhibitors of the serine proteases HGFA, matriptase and hepsin

2019

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“…Another subclass of TS inhibitors includes macrocyclic compounds which are structurally modified versions of the aforementioned peptide‐based TS inhibitors. These macrocyclic compounds were originally designed to improve the membrane permeability and oral bioavailability of TS inhibitors to increase their suitability for the clinical application .…”

Section: Drugs With Known Targetsmentioning

confidence: 99%

“…These macrocyclic compounds were originally designed to improve the membrane permeability and oral bioavailability of TS inhibitors to increase their suitability for the clinical application . Several studies have investigated the inhibitory effects of these macrocyclic TS inhibitors (EC 50 range: 1.5‐>20 μM) such as compound 24 [2.3.10]), as well as triazole‐based (EC 50 range, 3.8‐88.3 μM) (e.g. compound 8 [2.3.11]), oxadiazole‐based (EC 50 range, 2.5‐51.2 μM; e.g.…”

Section: Drugs With Known Targetsmentioning

confidence: 99%

Norovirus antivirals: Where are we now?

Netzler

Tuipulotu

White

2018

Medicinal Research Reviews

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Human noroviruses inflict a significant health burden on society and are responsible for approximately 699 million infections and over 200 000 estimated deaths worldwide each year. Yet despite significant research efforts, approved vaccines or antivirals to combat this pathogen are still lacking. Safe and effective antivirals are not available, particularly for chronically infected immunocompromised individuals, and for prophylactic applications to protect high-Med Res Rev. 2019;39:860-886. wileyonlinelibrary.com/journal/med 860 |

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

Cited by 12 publications

References 60 publications

GII.4 Norovirus Protease Shows pH-Sensitive Proteolysis with a Unique Arg-His Pairing in the Catalytic Site

GII.4 Norovirus Protease Shows pH-Sensitive Proteolysis with a Unique Arg-His Pairing in the Catalytic Site

Piperidine carbamate peptidomimetic inhibitors of the serine proteases HGFA, matriptase and hepsin

Norovirus antivirals: Where are we now?

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