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Article: Fragment-wise design of inhibitors to 3C proteinase from enterovirus 71

TitleFragment-wise design of inhibitors to 3C proteinase from enterovirus 71
Authors
Issue Date2016
Citation
Biochimica et Biophysica Acta (BBA) - General Subjects, 2016, v. 1860 n. 6, p. 1299-307 How to Cite?
AbstractBACKGROUND: Enterovirus 71 (EV71) is a causative agent of hand, foot and mouth disease (HFMD), which can spread its infection to central nervous and other systems with severe consequence. A key factor in the replication of EV71 is its 3C proteinase (3C(pro)), a significant drug target. Peptidomimetics were employed as inhibitors of this enzyme for developing antivirals. However, the peptide bonds in these peptidomimetics are a source of low bioavailability due to their susceptibility to protease digestion. To produce non-peptidomimetic inhibitors by replacing these peptide bonds, it would be important to gain better understanding on the contribution of each component to the interaction and potency. METHODS: A series of compounds of different lengths targeting 3C(pro) and having an α,β-unsaturated ester as the warhead were synthesized and their interactions with the enzyme were evaluated by complex structure analyses and potency assays for a better understanding on the relationship between potency and evolution of interaction. RESULTS: The P2 moiety of the compound would need to be oriented to interact in the S2 site in the substrate binding cleft and the P3-P4 moieties were required to generate sufficient potency. A hydrophobic terminal group will benefit the cellular uptake and improve the activity in vivo. CONCLUSIONS AND GENERAL SIGNIFICANCE: The data presented here provide a basis for designing a new generation of non-peptidomimetics to target EV71 3C(pro).
Persistent Identifierhttp://hdl.handle.net/10722/226636

 

DC FieldValueLanguage
dc.contributor.authorWu, C-
dc.contributor.authorZhang, L-
dc.contributor.authorLi, P-
dc.contributor.authorCai, Q-
dc.contributor.authorPeng, X-
dc.contributor.authorYin, K-
dc.contributor.authorChen, X-
dc.contributor.authorRen, H-
dc.contributor.authorZhong, S-
dc.contributor.authorWeng, Y-
dc.contributor.authorGuan, Y-
dc.contributor.authorChen, S-
dc.contributor.authorWu, J-
dc.contributor.authorLi, J-
dc.contributor.authorLin, T-
dc.date.accessioned2016-06-17T07:45:21Z-
dc.date.available2016-06-17T07:45:21Z-
dc.date.issued2016-
dc.identifier.citationBiochimica et Biophysica Acta (BBA) - General Subjects, 2016, v. 1860 n. 6, p. 1299-307-
dc.identifier.urihttp://hdl.handle.net/10722/226636-
dc.description.abstractBACKGROUND: Enterovirus 71 (EV71) is a causative agent of hand, foot and mouth disease (HFMD), which can spread its infection to central nervous and other systems with severe consequence. A key factor in the replication of EV71 is its 3C proteinase (3C(pro)), a significant drug target. Peptidomimetics were employed as inhibitors of this enzyme for developing antivirals. However, the peptide bonds in these peptidomimetics are a source of low bioavailability due to their susceptibility to protease digestion. To produce non-peptidomimetic inhibitors by replacing these peptide bonds, it would be important to gain better understanding on the contribution of each component to the interaction and potency. METHODS: A series of compounds of different lengths targeting 3C(pro) and having an α,β-unsaturated ester as the warhead were synthesized and their interactions with the enzyme were evaluated by complex structure analyses and potency assays for a better understanding on the relationship between potency and evolution of interaction. RESULTS: The P2 moiety of the compound would need to be oriented to interact in the S2 site in the substrate binding cleft and the P3-P4 moieties were required to generate sufficient potency. A hydrophobic terminal group will benefit the cellular uptake and improve the activity in vivo. CONCLUSIONS AND GENERAL SIGNIFICANCE: The data presented here provide a basis for designing a new generation of non-peptidomimetics to target EV71 3C(pro).-
dc.languageeng-
dc.relation.ispartofBiochimica et Biophysica Acta (BBA) - General Subjects-
dc.titleFragment-wise design of inhibitors to 3C proteinase from enterovirus 71-
dc.typeArticle-
dc.identifier.emailGuan, Y: yguan@hkucc.hku.hk-
dc.identifier.authorityGuan, Y=rp00397-
dc.identifier.doi10.1016/j.bbagen.2016.03.017-
dc.identifier.hkuros258357-
dc.identifier.volume1860-
dc.identifier.issue6-
dc.identifier.spage1299-
dc.identifier.epage307-

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