| Summary: | 碩士 === 長庚大學 === 醫學生物技術研究所 === 94 === Enterovirus 71 (EV71) is a highly infectious pathogen which causes hand, foot, and mouth disease (HFMD) in children. EV71 infection is usually accompanying with severe neurological complications and even death. Pyridyl imidazolidinone, discovered by computer-assisted drug design, is a novel class of potent and selective human enterovirus 71 inhibitor. In our previously report, BPR0Z-194, one of the pyridyl imidazolidinones, inhibited virus replication in the early stages, indicating that the compound can inhibit viral adsorption and involves in viral capsid protein function. Using BPR0Z-194 to select and characterize the drug-resistant viruses, we found some common mutations in VP1 region including Arg-22 to Gln, Asp-31 to Asn, Glu-98 to Lys, Tyr-116 to His, Glu-167 to Asp, Val-192 to Met, and Thr-240 to Ser. Here we used site-directed mutagenesis in enterovirus 71 infectious cDNA clone to generate the point mutation viruses. We also used eleven modified pyridyl imidazolidinones as chemical probes to investigate the interactions between compounds and EV71 VP1 protein. From drug susceptibility tests, D31N or E98K mutations in VP1 may let the VP1 hydrophobic pocket which the site of drug interaction become wider, so that more bulky compound can enter this pocket to interfere VP1-receptor binding. We also confirmed that V192M is a key mutation for resistance to the inhibitory effects of the drug. Moreover, from this study, we have identified several modified pyridyl imidazolidinones which is including
D101, D161 and D74 to inhibit the resistant viruses with V192M
mutation.
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