Artikel
Screening of electrophilic compounds as potential irreversible Mpro inhibitors
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Veröffentlicht: | 26. Mai 2004 |
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Gliederung
Text
All viral proteins required for coronavirus genome replication and transcription are encoded by the replicase gene. This gene encodes two replicative polyproteins (pp1a and pp1ab) which are extensively processed by viral proteases. The central and C-proximal regions are processed by the coronavirus main protease Mpro, a cysteine protease that is distantly related to picornaviral 3C proteases ([Ref. 1], [Ref. 2], [Ref. 3]). As already proven for 3C proteases the irreversible inhibition of coronaviral Mpros is considered to be a promising concept in antiviral drug development.[Ref. 4]
To evaluate electrophilic building blocks as warheads for irreversible Mpro inhibitors and to discover suitable lead structures we performed a first broad screening of various compounds (I-VI) which exhibit cysteine protease inhibiting properties [Fig. 1].
This was done on TGEV-M pro [Ref. 4] and SARS-M pro [Ref. 4] in an HPLC assay using different 15mer peptides as substrates [Ref. 5].Syntheses of the inhibitors and test results are discussed.
Furthermore, the development of spectrophotometric dilution assays using p-nitroanilide derived substrates is described. Based on the developed assays screenings of combinatorial inhibitor libraries are planned.
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