Design and synthesis of irreversible inhibitors of foot-and-mouth disease virus 3C protease

Rosell, Núria R. Roqué; Mokhlesi, Ladan; Milton, Nicholas; Sweeney, Trevor R.; Zunszain, Patricia A.; Curry, Stephen; Leatherbarrow, Robin J.

doi:10.1016/j.bmcl.2013.12.045

Cited by 9 publications

(7 citation statements)

References 33 publications

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“…It has been proposed that the FMDV 3C pro may be a good target for the development of an antiviral agent [ 20 ]. Furthermore, it was shown that compounds that resemble the peptide substrate can act as an efficient inhibitor of this protease.…”

Section: Discussionmentioning

confidence: 99%

Determinants of the VP1/2A junction cleavage by the 3C protease in foot-and-mouth disease virus-infected cells

Kristensen

Normann

Gullberg

et al. 2017

Journal of General Virology

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The foot-and-mouth disease virus (FMDV) capsid precursor, P1-2A, is cleaved by FMDV 3C protease to yield VP0, VP3, VP1 and 2A. Cleavage of the VP1/2A junction is the slowest. Serotype O FMDVs with uncleaved VP1-2A (having a K210E substitution in VP1; at position P2 in cleavage site) have been described previously and acquired a second site substitution (VP1 E83K) during virus rescue. Furthermore, introduction of the VP1 E83K substitution alone generated a second site change at the VP1/2A junction (2A L2P, position P2′ in cleavage site). These virus adaptations have now been analysed using next-generation sequencing to determine sub-consensus level changes in the virus; this revealed other variants within the E83K mutant virus population that changed residue VP1 K210. The construction of serotype A viruses with a blocked VP1/2A cleavage site (containing K210E) has now been achieved. A collection of alternative amino acid substitutions was made at this site, and the properties of the mutant viruses were determined. Only the presence of a positively charged residue at position P2 in the cleavage site permitted efficient cleavage of the VP1/2A junction, consistent with analyses of diverse FMDV genome sequences. Interestingly, in contrast to the serotype O virus results, no second site mutations occurred within the VP1 coding region of serotype A viruses with the blocked VP1/2A cleavage site. However, some of these viruses acquired changes in the 2C protein that is involved in enterovirus morphogenesis. These results have implications for the testing of potential antiviral agents targeting the FMDV 3C protease.

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Section: Discussionmentioning

confidence: 99%

Determinants of the VP1/2A junction cleavage by the 3C protease in foot-and-mouth disease virus-infected cells

Kristensen

Normann

Gullberg

et al. 2017

Journal of General Virology

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“…Recently, there has been a renewed interest in 92 and similar peptidic compounds with attached Michael acceptors, for the treatment of enterovirus-71, noroviruses, and foot and mouth disease that have 3C proteases resembling HRV-3CP. 52 …”

Section: αβ-Unsaturated Esters and Lactonesmentioning

confidence: 99%

“…Compound 92 made it through initial phase II trials with a good safety profile and moderate efficacy but failed in larger phase II trials due to low efficacy. Recently, there has been a renewed interest in 92 and similar peptidic compounds with attached Michael acceptors for the treatment of enterovirus-71, noroviruses, and foot and mouth disease that have 3C proteases resembling HRV-3CP …”

Section: αβ-Unsaturated Esters and Lactonesmentioning

confidence: 99%

Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions

et al. 2016

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Although Michael acceptors display a potent and broad spectrum of bioactivity, they have largely been ignored in drug discovery because of their presumed indiscriminate reactivity. As such, a dearth of information exists relevant to the thiol reactivity of natural products and their analogs possessing this moiety. In the midst of recently approved acrylamide-containing drugs, it is clear that a good understanding of the hetero-Michael addition reaction and the relative reactivities of biological thiols with Michael acceptors under physiological conditions is needed for the design and use of these compounds as biological tools and potential therapeutics. This perspective provides information that will contribute to this understanding, such as kinetics of thiol addition reactions, bioactivities, as well as steric and electronic factors that influence the electrophilicity and reversibility of Michael acceptors. This perspective is focused on α,β-unsaturated carbonyls given their preponderance in bioactive natural products.

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“…FMDV 3C pro processes 10 of 13 cleavage sites on the polyprotein, making this enzyme an attractive target for antiviral drugs. The active site of FMDV 3C pro contains a chymotrypsin-like catalytic triad composed of Cys163-His46-Asp84 with a Cys142 flap for structural stabilization, which is structurally more specific to FMDV than other picornaviruses [ 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

Andrographolide and Deoxyandrographolide Inhibit Protease and IFN-Antagonist Activities of Foot-and-Mouth Disease Virus 3Cpro

Theerawatanasirikul

Lueangaramkul

Thangthamniyom

et al. 2022

Animals

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Foot-and mouth-disease (FMD) caused by the FMD virus (FMDV) is highly contagious and negatively affects livestock worldwide. The control of the disease requires a combination of measures, including vaccination; however, there is no specific treatment available. Several studies have shown that plant-derived products with antiviral properties were effective on viral diseases. Herein, antiviral activities of andrographolide (AGL), deoxyandrographolide (DAG), and neoandrographolide (NEO) against FMDV serotype A were investigated using an in vitro cell-based assay. The results showed that AGL and DAG inhibited FMDV in BHK-21 cells. The inhibitory effects of AGL and DAG were evaluated by RT-qPCR and exhibited EC50 values of 52.18 ± 0.01 µM (SI = 2.23) and 36.47 ± 0.07 µM (SI = 9.22), respectively. The intracellular protease assay revealed that AGL and DAG inhibited FMDV 3Cpro with IC50 of 67.43 ± 0.81 and 25.58 ± 1.41 µM, respectively. Additionally, AGL and DAG significantly interfered with interferon (IFN) antagonist activity of the 3Cpro by derepressing interferon-stimulating gene (ISGs) expression. The molecular docking confirmed that the andrographolides preferentially interacted with the 3Cpro active site. However, NEO had no antiviral effect in any of the assays. Conclusively, AGL and DAG inhibited FMDV serotype A by interacting with the 3Cpro and hindered its protease and IFN antagonist activities.

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Design and synthesis of irreversible inhibitors of foot-and-mouth disease virus 3C protease

Cited by 9 publications

References 33 publications

Determinants of the VP1/2A junction cleavage by the 3C protease in foot-and-mouth disease virus-infected cells

Determinants of the VP1/2A junction cleavage by the 3C protease in foot-and-mouth disease virus-infected cells

Covalent Modifiers: A Chemical Perspective on the Reactivity of α,β-Unsaturated Carbonyls with Thiols via Hetero-Michael Addition Reactions

Andrographolide and Deoxyandrographolide Inhibit Protease and IFN-Antagonist Activities of Foot-and-Mouth Disease Virus 3Cpro

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