gms | German Medical Science

International Conference on SARS - one year after the (first) outbreak

08. - 11.05.2004, Lübeck

Article

Send article

Screening of electrophilic compounds as potential irreversible Mpro inhibitors

Poster

Search Medline for

  • Alexander Breuning - Institut für Pharmazie und LMC, Würzburg, Germany
  • Radim Vicik - Institut für Pharmazie und LMC, Würzburg, Germany
  • Carsten Schmuck - Institut für Organische Chemie, Würzburg, Germany
  • John Ziebuhr - Institut für Virologie und Immunbiologie, Universität Würzburg, Würzburg, Germany
  • corresponding author presenting/speaker Tanja Schirmeister - Institut für Pharmazie und LMC, Würzburg, Germany

International Conference on SARS - one year after the (first) outbreak. Lübeck, 08.-11.05.2004. Düsseldorf, Köln: German Medical Science; 2004. Doc04sarsP9.02

The electronic version of this article is the complete one and can be found online at: http://www.egms.de/en/meetings/sars2004/04sars124.shtml

Published: May 26, 2004

© 2004 Breuning et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.en). You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.

Outline

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 ([1], [2], [3]). As already proven for 3C proteases the irreversible inhibition of coronaviral Mpros is considered to be a promising concept in antiviral drug development.[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 [4] and SARS-M pro [4] in an HPLC assay using different 15mer peptides as substrates [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.

Outline

References

1.
K. Anand, G. J. Palm, J. R. Mesters, S. G. Siddell, J. Ziebuhr, R. Hilgenfeld, EMBO J. 2002, 21, 3213
2.
H. Yang, M. Yang, Y. Ding, Y. Liu, Z. Lou, Z. Zhou, L. Sun, L. Mo, S. Ye, H. Pang, G. Gao, K. Anand, M. Bartlam, R. Hilgenfeld, Z. Rao, PNAS, 2003, 100, 13190
3.
J. Ziebuhr, E. J. Snijder, A. E. Gorbalenya, J. Gen. Virol. 2000, 81, 853
4.
K. Anand, J. Ziebuhr, P. Wadhwani, J. Mesters, R. Hilgenfeld, Science 2003, 300, 1763
5.
J. Ziebuhr, G. Heusipp, S. G. Siddell, J. Virol. 1997, 71, 3992.