Putative structural rearrangements associated with the interaction of macrocyclic inhibitors with norovirus 3CL protease

Galasiti Kankanamalage, Anushka C.; Weerawarna, Pathum M.; Rathnayake, Athri D.; Kim, Yunjeong; Mehzabeen, Nurjahan; Battaile, Kevin P.; Lovell, Scott; Chang, Kyeong‐Ok; Groutas, William C.

doi:10.1002/prot.25682

Title: Putative structural rearrangements associated with the interaction of macrocyclic inhibitors with norovirus 3CL protease

Journal Article · Mon Mar 18 00:00:00 EDT 2019 · Proteins

DOI:https://doi.org/10.1002/prot.25682· OSTI ID:1529622

Galasiti Kankanamalage, Anushka C. ^[1]; Weerawarna, Pathum M. ^[1]; Rathnayake, Athri D. ^[1]; Kim, Yunjeong ^[2]; Mehzabeen, Nurjahan ^[3]; Battaile, Kevin P. ^[4]; Lovell, Scott ^[3]; Chang, Kyeong‐Ok ^[2];

^[1]

Wichita State Univ., Wichita, KS (United States)
Kansas State Univ., Manhattan, KS (United States)
Univ. of Kansas, Lawrence, KS (United States)
Argonne National Lab. (ANL), Argonne, IL (United States)

Human noroviruses are the primary cause of outbreaks of acute gastroenteritis worldwide. The problem is further compounded by the current lack of norovirus-specific antivirals or vaccines. Noroviruses have a single-stranded, positive sense 7 to 8 kb RNA genome which encodes a polyprotein precursor that is processed by a virus-encoded 3C-like cysteine protease (NV 3CLpro) to generate at least six mature nonstructural proteins. Processing of the polyprotein is essential for virus replication, consequently, NV 3CLpro has emerged as an attractive target for the discovery of norovirus therapeutics and prophylactics. We have recently described the structure-based design of macrocyclic transition state inhibitors of NV 3CLpro. In order to gain insight and understanding into the interaction of macrocyclic inhibitors with the enzyme, as well as probe the effect of ring size on pharmacological activity and cellular permeability, additional macrocyclic inhibitors were synthesized and high resolution cocrystal structures determined. The results of our studies tentatively suggest that the macrocyclic scaffold may hamper optimal binding to the active site by impeding concerted cross-talk between the S2 and S4 subsites.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Contributing Organization:: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)

Grant/Contract Number:: AC02–06CH11357; P30GM110761; AI109039; AC02‐06CH11357

OSTI ID:: 1529622

Alternate ID(s):: OSTI ID: 1504300

Journal Information:: Proteins, Vol. 87, Issue 7; ISSN 0887-3585

Publisher:: WileyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 4 works

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active site
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structural rearrangement

Title: Putative structural rearrangements associated with the interaction of macrocyclic inhibitors with norovirus 3CL protease

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