TAILIEUCHUNG - Báo cáo khoa học: Mutant recombinant serpins as highly specific inhibitors of human kallikrein 14

The reactive center loop (RCL) of serpins plays an essential role in the inhibition mechanism acting as a substrate for their target proteases. Chan-ges within the RCL sequence modulate the specificity and reactivity of the serpin molecule. Recently, we reported the construction of a1-antichymo- | ềFEBS Journal Mutant recombinant serpins as highly specific inhibitors of human kallikrein 14 Loyse M. Felber1 2 Christoph Kundig1 2 Carla A. Borgono3 Jair R. Chagas4 Andrea Tasinato1 Patrice Jichlinski1 Christian M. Gygi1 Hans-Jurg Leisinger1 Eleftherios P. Diamandis3 David Deperthes1 2 and Sylvain M. Cloutier1 2 1 Urology Research Unit Department of Urology CHUV Epalinges Switzerland 2 MedicalDiscovery SA Epalinges Switzerland 3 Department of Pathology and Laboratory Medicine Mount Sinai Hospital Toronto Canada 4 Centro Interdisciplinar de Investigacao Bioquimica Universidade de Mogi das Cruzes Brazil Keywords inhibitor kallikrein protease serpin Correspondence D. Deperthes Urology Research Unit MedicalDiscovery SA Biopole Ch. Croisettes 22 CH-1066 Epalinges Switzerland Fax 41 21 6547133 Tel 41 21 6547130 E-mail Received 15 September 2005 revised 1 March 2006 accepted 3 April 2006 doi The reactive center loop RCL of serpins plays an essential role in the inhibition mechanism acting as a substrate for their target proteases. Changes within the RCL sequence modulate the specificity and reactivity of the serpin molecule. Recently we reported the construction of a1-antichymo-trypsin ACT variants with high specificity towards human kallikrein 2 hK2 Cloutier SM Kundig C Felber LM Fattah OM Chagas JR Gygi CM Jichlinski P Leisinger HJ Deperthes D 2004 Eur J Biochem 271 607-613 by changing amino acids surrounding the scissile bond of the RCL and obtained specific inhibitors towards hK2. Based on this approach we developed highly specific recombinant inhibitors of human kallikrein 14 hK14 a protease correlated with increased aggressiveness of prostate and breast cancers. In addition to the RCL permutation with hK14 phage display-selected substrates E8 LQRAI and G9 TVDYA Felber LM Borgono CA Cloutier SM Kundig C Kishi T Chagas JR Jichlinski P Gygi CM Leisinger HJ Diamandis EP Deperthes D 2005 Biol Chem 386 .

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