Cyanohydrin as an Anchoring Group for Potent and Selective Inhibitors of Enterovirus 71 3C Protease

A series of tripeptidyl transition state inhibitors with new P1 and warhead moieties were synthesized and evaluated in a GI-1 norovirus replicon system and against GII-4 and GI-1 norovirus proteases. Compound 19, containing a 6-membered ring at the P1 position and a reactive aldehyde warhead exhibited sub-micromolar replicon inhibition. Retaining the same peptidyl scaffold, several reactive warheads were tested for protease inhibition and norovirus replicon inhibition. Of the six that were synthesized and tested, compounds 42, 43, and 45 potently inhibited the protease in biochemical assay and GI-1 norovirus replicon in the nanomolar range.

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“…Piperidinone intermediate 9 was prepared from natural glutamic acid 8 by following previously published procedures. 8 …”

Section: Evaluation Of New P1 Moietiesmentioning

confidence: 99%

Synthesis and antiviral evaluation of novel peptidomimetics as norovirus protease inhibitors

Amblard

Zhou

Liu

et al. 2018

Bioorganic & Medicinal Chemistry Letters

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“…We developed a highly efficient assay (12,13) and discovered a series of potent anti-EV71 PIs targeting EV71 3C pro (14)(15)(16)(17)(18). Among them, NK-1.8k (a peptidyl aldehyde derivative) and compound 9 and NK-1.9k (cyanohydrin derivatives) have the highest potencies against EV71 infection with good pharmacological properties, but they still exhibit distinct features.…”

mentioning

confidence: 99%

Structure of the Enterovirus 71 3C Protease in Complex with NK-1.8k and Indications for the Development of Antienterovirus Protease Inhibitor

Wang

Cao

Zhai

et al. 2017

Antimicrob Agents Chemother

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Hand-foot-and-mouth disease (HFMD), caused by enterovirus, is a threat to public health worldwide. To date, enterovirus 71 (EV71) has been one of the major causative agents of HFMD in the Pacific-Asia region, and outbreaks with EV71 cause millions of infections. However, no drug is currently available for clinical therapeutics. In our previous works, we developed a set of protease inhibitors (PIs) targeting the EV71 3C protease (3C pro ). Among these are NK-1.8k and NK-1.9k, which have various active groups and high potencies and selectivities. In the study described here, we determined the structures of the PI NK-1.8k in complex with wild-type (WT) and drug-resistant EV71 3C pro . Comparison of these structures with the structure of unliganded EV71 3C pro and its complex with AG7088 indicated that the mutation of N69 to a serine residue destabilized the S2 pocket. Thus, the mutation influenced the cleavage activity of EV71 3C pro and the inhibitory activity of NK-1.8k in an in vitro protease assay and highlighted that site 69 is an additional key site for PI design. More information for the optimization of the P1= to P4 groups of PIs was also obtained from these structures. Together with the results of our previous works, these in-depth results elucidate the inhibitory mechanism of PIs and shed light to develop PIs for the clinical treatment of infections caused by EV71 and other enteroviruses.KEYWORDS EV71, protease, inhibitor, crystal structure, mechanism H and-foot-and-mouth disease (HFMD) is a common viral illness among infants and young children that causes fever, sore throat, blisters, pharyngitis, mouth ulcers, and a rash on the hands and feet (1, 2). Enterovirus 71 (EV71) has been the main causative agent of HFMD in recent years. Unfortunately, no drugs for the treatment of this disease are available. EV71 is classified as a member of Enterovirus species A within the genus Enterovirus of the Picornaviridae family (3). In the virus replication cycle, the 7.4-kb positive-sense, single-stranded RNA genome of EV71 is translated into a polyprotein which is subdivided into three primary precursors, P1, P2, and P3. Four structural proteins, VP1 to VP4, derived from the P1 portion, form the capsid of the mature virion (4), and the P2 and P3 regions are cleaved by viral proteases, forming seven individual nonstructural proteins, 2A, 2B, 2C, 3A, 3B, 3C, and 3D (5, 6). The correct replication of EV71 is dependent on the effective cleavage of the viral polyprotein by viral 2A protease (2A pro ) and 3C protease (3C pro ) (7). Of these two proteases, 3C pro not only takes major responsibility for polyprotein cleavage, with the exception that 2A pro is responsible for the cleavage of VP1/2A and 3C/3D, but also plays multiple roles in various biological processes (8).EV71 3C pro is a classical cysteine protease. Cysteine proteases are a large family containing many members functioning in various physiological processes (9). The

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“…The 12 crystal structures of EV‐A71 3C pro bound with inhibitors from the RCSB PDB database are 4GHT, 5BPE, 5C1U, 5C1X, 5C1Y, 5C20, 5DP5, 5DP6, 5DP7, 5DP8, 5DP9, and 5DPA (Table ). Protein preparation wizard in MOE software was used to prepare the proteins.…”

Section: Methodsmentioning

confidence: 99%

“…Several substrate based EV‐A71 3C pro inhibitors have been identified . However, to the best of our knowledge, pharmacophore and three‐dimensional quantitative structure‐activity relationships (3D‐QSAR) models for EV‐A71 3C pro inhibitor have not been reported to date.…”

Section: Introductionmentioning

confidence: 99%

3D‐quantitative structure‐activity relationship study for the design of novel enterovirus A71 3C protease inhibitors

Nie

Zhang

et al. 2018

Chem Biol Drug Des

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A three-dimensional quantitative structure-activity relationships model of enterovirus A71 3C protease inhibitors was constructed in this study. The protein-ligand interaction fingerprint was analyzed to generate a pharmacophore model. A predictive and reliable three-dimensional quantitative structure-activity relationships model was built based on the Flexible Alignment of AutoGPA. Moreover, three novel compounds (I-III) were designed and evaluated for their biochemical activity against 3C protease and anti-enterovirus A71 activity in vitro. III exhibited excellent inhibitory activity (IC = 0.031 ± 0.005 μM, EC = 0.036 ± 0.007 μM). Thus, this study provides a useful quantitative structure-activity relationships model to develop potent inhibitors for enterovirus A71 3C protease.

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Cyanohydrin as an Anchoring Group for Potent and Selective Inhibitors of Enterovirus 71 3C Protease

Cited by 55 publications

References 40 publications

Synthesis and antiviral evaluation of novel peptidomimetics as norovirus protease inhibitors

Synthesis and antiviral evaluation of novel peptidomimetics as norovirus protease inhibitors

Structure of the Enterovirus 71 3C Protease in Complex with NK-1.8k and Indications for the Development of Antienterovirus Protease Inhibitor

3D‐quantitative structure‐activity relationship study for the design of novel enterovirus A71 3C protease inhibitors

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