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Lidiya Angelova-Duleva PhD thesis
1. Characterization of a protease inhibitor PISC-2002 wit h anti-influenza virus activity isolated from Streptomyces chromofuscus Lidiya Angelova-Duleva, PhD
6. Genus Streptomyces unique mycelial, sporulating life cycle products with broad medical application Protease Inhibitors FLU Proteolytic cleavage of HA from subtilizin-like host proteases (H5 and H7) or trypsin-like host proteases (other H types) INFECTION Project Overview
7. Cell toxicity and virus-inhibitory effects of cell-free extracts from Streptomyces on human (H3N2) and bird (H7N1) virus replication in MDCK cells * n. t. – not tested Strain Cell toxicity TC50 (µg ml-1) A/Rostock (H7N1 ) A/Aichi (H3N2) ED 50 (µg ml-1) SI ED 50 (µg ml-1) SI Streptomyces sp. 3 В (30) >1000 32 > 32.0 32 32.0 Streptomyces sp.19-Б 67 17 4.0 5 13.0 Streptomyces sp. ДЕБ-3 25 8 3.2 8 3.2 Streptomyces chromofuscus 34-1 >1600 12.5 128 23 70 Streptomyces galbus var. achromogenes 695 0.3 > 0.3 - n. t. n. t. Streptomyces galbus var. achromogenes 695-2-206 0.3 >0.3 - n. t. n. t. Streptomyces sp. A 12 >1670 > 1670 - n. t. n. t. Streptomyces sp. 712 183 11.4 16.0 11.4 16.0 Rimantadin >32.0 0.2 2. 5 mg/ml >160 0.5 3.0 mg/ml >64.0 ε-AKK 50.0 mg/ml 25.0 16.6
8. Purification of PISC-2002 Ammonium Sulphate Precipitation (80%, 24 h , 4°С) Anion E xchange S eparation Reversed Phase Chromatography Analytical RP-HPLC
11. Homology between PISC-2002 and SSI family inhibitors Amino acid sequence a Main fraction. b Minor fraction. Species ( proteinase inhibitor ) S. chromofuscus (PISC-2002) a S. chromofuscus (PISC-2002) b AS L PAV SALVLTV S L PAV SALVLTV S. lividans (SLPI (STI1)) S L YAP SALVLTV GHG S. longisporus (STI 2) AS L YAP SALVLTV GHG S. coelicolor A3 (SIL 3) S L Y A P SALVLTV GHG
14. Virus-inhibitory effect of PISC-2002 on the reproduction of A/Rostock (H7N1) (one cycle of viral replication)
15. Effect of the protease inhibitor on the survival rate of mice in the experimental influenza A/Aichi-a infection
16. Infectious titer in mice lungs in the experimental influenza A/Aichi-a infection
17. PISC-2002 protects mice from infection (morphological changes in mice lungs at the 9-th day of influenza infection) a – non infected untreated mice b – infected untreated mice c – infected mice treated with P ISC-2002 a b c