The Proteasome as a Drug Target in the Metazoan Pathogen, Schistosoma mansoni

被引:27
作者
Bibo-Verdugo, Betsaida [1 ,2 ,3 ]
Wang, Steven C. [1 ,2 ,4 ]
Almaliti, Jehad [5 ,6 ]
Ta, Anh P. [2 ]
Jiang, Zhenze [2 ,7 ]
Wong, Derek A. [2 ]
Lietz, Christopher B. [2 ]
Suzuki, Brian M. [1 ,2 ]
El-Saldary, Nelly [1 ,2 ]
Hook, Vivian [2 ]
Salvesen, Guy S. [3 ]
Gerwick, William H. [1 ,2 ,5 ]
Caffrey, Conor R. [1 ,2 ]
O'Donoghue, Anthony J. [1 ,2 ]
机构
[1] Univ Calif San Diego, Ctr Discovery & Innovat Parasit Dis, 9500 Gilman Dr, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, 9500 Gilman Dr, La Jolla, CA 92093 USA
[3] Sanford Burnham Prebys Med Discovery Inst, 10901 North Torrey Pines Rd, La Jolla, CA 92037 USA
[4] Univ Calif San Diego, Div Biol Sci, 9500 Gilman Dr, La Jolla, CA 92093 USA
[5] Univ Calif San Diego, Scripps Inst Oceanog, 9500 Gilman Dr, La Jolla, CA 92093 USA
[6] Univ Jordan, Dept Pharmaceut Sci, Fac Pharm, Amman 11942, Jordan
[7] Univ Calif San Diego, Dept Chem & Biochem, 9500 Gilman Dr, La Jolla, CA 92093 USA
关键词
proteasome; Schistosoma; schistosomiasis; bortezomib; catfilzomib; carmaphycin; MG132; INHIBITOR; CHEMOTHERAPY; APOPTOSIS; PRAZIQUANTEL; SPECIFICITY; INFECTIONS; VALIDATION; POTENT; SITES; DEATH;
D O I
10.1021/acsinfecdis.9b00237
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Proteases are fundamental to successful parasitism, including that of the schistosome flatworm parasite, which causes the disease schistosomiasis in 200 million people worldwide. The proteasome is receiving attention as a potential drug target for treatment of a variety of infectious parasitic diseases, but it has been understudied in the schistosome. Adult Schistosoma mansoni were incubated with 1 mu M concentrations of the proteasome inhibitors bortezomib, carfilzomib, and MG132. After 24 h, bortezomib and carfilzomib decreased worm motility by more than 85% and endogenous proteasome activity by >75%, and after 72 h, they increased caspase activity by >4.5-fold. The association between the engagement of the proteasome target and the phenotypic and biochemical effects recorded encouraged the chromatographic enrichment of the S. mansoni proteasome (Sm20S). Activity assays with fluorogenic proteasome substrates revealed that Sm20S contains caspase-type (beta 1), trypsin-type (beta 2), and chymotrypsin-type (beta 5) activities. Sm20S was screened with 11 peptide epoxyketone inhibitors derived from the marine natural product carmaphycin B. Analogue 17 was 27.4-fold less cytotoxic to HepG2 cells than carmaphycin B and showed equal potency for the beta 5 subunits of Sm20S, human constitutive proteasome, and human immunoproteasome. However, this analogue was 13.2-fold more potent at targeting Sm20S beta 2 than it was at targeting the equivalent subunits of the human enzymes. Furthermore, 1 mu M 17 decreased both worm motility and endogenous Sm20S activity by more than 90% after 24 h. We provide direct evidence of the proteasome's importance to schistosome viability and identify a lead for which future studies will aim to improve the potency, selectivity, and safety.
引用
收藏
页码:1802 / 1812
页数:21
相关论文
共 64 条
[1]   Schistosomiasis mansoni: Novel chemotherapy using a cysteine protease inhibitor [J].
Abdulla, Maha-Hamadien ;
Lim, Kee-Chong ;
Sajid, Mohammed ;
McKerrow, James H. ;
Caffrey, Conor R. .
PLOS MEDICINE, 2007, 4 (01) :130-138
[2]   Drug Discovery for Schistosomiasis: Hit and Lead Compounds Identified in a Library of Known Drugs by Medium-Throughput Phenotypic Screening [J].
Abdulla, Maha-Hamadien ;
Ruelas, Debbie S. ;
Wolff, Brian ;
Snedecor, June ;
Lim, Kee-Chong ;
Xu, Fengyun ;
Renslo, Adam R. ;
Williams, Janice ;
McKerrow, James H. ;
Caffrey, Conor R. .
PLOS NEGLECTED TROPICAL DISEASES, 2009, 3 (07)
[3]   Potent and selective inhibitors of the proteasome: Dipeptidyl boronic acids [J].
Adams, J ;
Behnke, M ;
Chen, SW ;
Cruickshank, AA ;
Dick, LR ;
Grenier, L ;
Klunder, JM ;
Ma, YT ;
Plamondon, L ;
Stein, RL .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1998, 8 (04) :333-338
[5]   Regulated protein turnover: snapshots of the proteasome in action [J].
Bhattacharyya, Sucharita ;
Yu, Houqing ;
Mim, Carsten ;
Matouschek, Andreas .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2014, 15 (02) :122-133
[6]   Targeting proteasomes in infectious organisms to combat disease [J].
Bibo-Verdugo, Betsaida ;
Jiang, Zhenze ;
Caffrey, Conor R. ;
O'Donoghue, Anthony J. .
FEBS JOURNAL, 2017, 284 (10) :1503-1517
[7]   Chemotherapy of schistosomiasis: present and future [J].
Caffrey, Conor R. .
CURRENT OPINION IN CHEMICAL BIOLOGY, 2007, 11 (04) :433-439
[8]   Cysteine proteases as digestive enzymes in parasitic helminths [J].
Caffrey, Conor R. ;
Goupil, Louise ;
Rebello, Karina M. ;
Dalton, John P. ;
Smith, David .
PLOS NEGLECTED TROPICAL DISEASES, 2018, 12 (08)
[9]  
Caffrey CR, 2015, FUTURE MED CHEM, V7, P675, DOI [10.4155/FMC.15.27, 10.4155/fmc.15.27]
[10]   SCHISTOSOMA-MANSONI - SIMPLIFIED METHOD FOR PRODUCTION OF SCHISTOSOMULES [J].
COLLEY, DG ;
WIKEL, SK .
EXPERIMENTAL PARASITOLOGY, 1974, 35 (01) :44-51