Structural basis of mercury- and zinc-conjugated complexes as SARS-CoV 3C-like protease inhibitors

Lee, Cheng-Chung; Kuo, Chih-Jung; Hsu, Min-Feng; Liang, Po-Huang; Fang, Jim-Min; Shie, Jiun-Jie; Wang, Andrew H.-J.

doi:10.1016/j.febslet.2007.10.048

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Volume 581, Issue 28 , Pages 5454-5458, 27 November 2007

Structural basis of mercury- and zinc-conjugated complexes as SARS-CoV 3C-like protease inhibitors

Edited by Richard Cogdell

Cheng-Chung Lee
- Structural Biology Program, Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 11221, Taiwan
- Institute of Biological Chemistry, Academia Sinica, Taipei 11529, Taiwan
- National Core Facility of High-Throughput Protein Crystallography, Academia Sinica, Taipei 11529, Taiwan
Chih-Jung Kuo
- Institute of Biological Chemistry, Academia Sinica, Taipei 11529, Taiwan
- Taiwan International Graduate Program, Academia Sinica, Taipei 11529, Taiwan
Min-Feng Hsu
- Institute of Biological Chemistry, Academia Sinica, Taipei 11529, Taiwan
- National Core Facility of High-Throughput Protein Crystallography, Academia Sinica, Taipei 11529, Taiwan
Po-Huang Liang
- National Core Facility of High-Throughput Protein Crystallography, Academia Sinica, Taipei 11529, Taiwan
- The Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan
- Taiwan International Graduate Program, Academia Sinica, Taipei 11529, Taiwan
- Institute of Biochemical Sciences, National Taiwan University, Taipei 10617, Taiwan
Jim-Min Fang
- The Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan
- Department of Chemistry, National Taiwan University, Taipei 10617, Taiwan
Jiun-Jie Shie
- The Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan
Andrew H.-J. Wang
- Structural Biology Program, Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 11221, Taiwan
- Institute of Biological Chemistry, Academia Sinica, Taipei 11529, Taiwan
- National Core Facility of High-Throughput Protein Crystallography, Academia Sinica, Taipei 11529, Taiwan
- The Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan
- Taiwan International Graduate Program, Academia Sinica, Taipei 11529, Taiwan
- Institute of Biochemical Sciences, National Taiwan University, Taipei 10617, Taiwan
- Corresponding author. Address: Institute of Biological Chemistry, Academia Sinica, Taipei 11529, Taiwan. Fax: +886 2 2788 2043.

Received 24 September 2007; received in revised form 25 October 2007; accepted 25 October 2007. published online 02 November 2007.

Abstract

Five active metal-conjugated inhibitors (PMA, TDT, EPDTC, JMF1586 and JMF1600) bound with the 3C-like protease of severe acute respiratory syndrome (SARS)-associated coronavirus were analyzed crystallographically. The complex structures reveal two major inhibition modes: Hg²⁺-PMA is coordinated to C⁴⁴, M⁴⁹ and Y⁵⁴ with a square planar geometry at the S3 pocket, whereas each Zn²⁺ of the four zinc-inhibitors is tetrahedrally coordinated to the H⁴¹–C¹⁴⁵ catalytic dyad. For anti-SARS drug design, this Zn²⁺-centered coordination pattern would serve as a starting platform for inhibitor optimization.

Abbreviations: BABIM, bis(5-amidino-2-benzimidazolyl) methane, EPDTC, N-ethyl-N-phenyldithiocarbamic acid zinc, ESI-MS, electrospray ionization mass spectrometry, JMF1586, bis(l-aspartato-N,O) zinc(II) ethanate, JMF1600, (nitrilotriacetato-N,O) zinc(II) acetate, NMR, nuclear magnetic resonance, PMA, phenylmercuric acetate, TDT, toluene-3,4-dithiolato zinc