Two key cathepsins, TgCPB and TgCPL, are targeted by the vinyl sulfone inhibitor K11777 in in vitro and in vivo models of toxoplasmosis

Although toxoplasmosis is one of the most common parasitic infections worldwide, therapeutic options remain limited. Cathepsins, proteases that play key roles in the pathogenesis of toxoplasmosis and many other protozoan infections, are important potential therapeutic targets. Because both TgCPB and...

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Published in:PloS one 2018-03, Vol.13 (3), p.e0193982-e0193982
Main Authors: Chaparro, Juan D, Cheng, Timmy, Tran, Uyen Phuong, Andrade, Rosa M, Brenner, Sara B T, Hwang, Grace, Cohn, Shara, Hirata, Ken, McKerrow, James H, Reed, Sharon L
Format: Article
Language:English
Subjects:
Analysis
Animals
Antiparasitic agents
Antiparasitic Agents - pharmacology
Biocompatibility
Biology and Life Sciences
Cathepsins
Cathepsins - metabolism
Chemical compounds
Chickens
Development and progression
Dipeptides - pharmacology
Drug therapy
Embryos
Entamoeba histolytica
Fetuses
Fibroblasts
Fibroblasts - drug effects
Fibroblasts - metabolism
Health aspects
Humans
Infections
Infectious diseases
Inhibition
Inhibitors
Medicine
Medicine and Health Sciences
Parasites
Parasitic diseases
Pathogenesis
Pathology
Pharmacokinetics
Pharmacological research
Pharmacology
Pharmacy
Phenylalanine - analogs & derivatives
Physical Sciences
Physiological aspects
Piperazine
Piperazines
Proteins
Protozoa
Protozoan Proteins - metabolism
Regression analysis
Sulfones
Sulfones - antagonists & inhibitors
Tachyzoites
Therapeutic applications
Tosyl Compounds
Toxicity
Toxoplasma gondii
Toxoplasmosis
Toxoplasmosis - drug therapy
Toxoplasmosis - metabolism
Trypanosoma cruzi
Vinyl Compounds - pharmacology
Vinyl sulfone
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creator Chaparro, Juan D
Cheng, Timmy
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Andrade, Rosa M
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Cohn, Shara
Hirata, Ken
McKerrow, James H
Reed, Sharon L
description Although toxoplasmosis is one of the most common parasitic infections worldwide, therapeutic options remain limited. Cathepsins, proteases that play key roles in the pathogenesis of toxoplasmosis and many other protozoan infections, are important potential therapeutic targets. Because both TgCPB and TgCPL play a role in T. gondii invasion, we evaluated the efficacy of the potent, irreversible vinyl sulfone inhibitor, K11777 (N-methyl-piperazine-Phe-homoPhe-vinylsulfone-phenyl). The inhibitor's toxicity and pharmacokinetic profile have been well-studied because of its in vitro and in vivo activity against a number of parasites. We found that it inhibited both TgCPB (EC50 = 114 nM) and TgCPL (EC50 = 71 nM) in vitro. K11777 also inhibited invasion of human fibroblasts by RH tachyzoites by 71% (p = 0.003) and intracellular replication by >99% (p
doi_str_mv 10.1371/journal.pone.0193982
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Cathepsins, proteases that play key roles in the pathogenesis of toxoplasmosis and many other protozoan infections, are important potential therapeutic targets. Because both TgCPB and TgCPL play a role in T. gondii invasion, we evaluated the efficacy of the potent, irreversible vinyl sulfone inhibitor, K11777 (N-methyl-piperazine-Phe-homoPhe-vinylsulfone-phenyl). The inhibitor's toxicity and pharmacokinetic profile have been well-studied because of its in vitro and in vivo activity against a number of parasites. We found that it inhibited both TgCPB (EC50 = 114 nM) and TgCPL (EC50 = 71 nM) in vitro. K11777 also inhibited invasion of human fibroblasts by RH tachyzoites by 71% (p = 0.003) and intracellular replication by &gt;99% (p&lt;0.0001). In vivo, a single dose of K11777 led to 100% survival of chicken embryos in an model of acute toxoplasmosis (p = 0.015 Cox regression analysis). 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Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing &amp; Allied Health Database (Alumni Edition)</collection><collection>Meteorological &amp; Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agriculture Science Database</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>ProQuest Biological Science Journals</collection><collection>Engineering Database</collection><collection>Nursing &amp; Allied Health Premium</collection><collection>ProQuest advanced technologies &amp; aerospace journals</collection><collection>ProQuest Advanced Technologies &amp; Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials science collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chaparro, Juan D</au><au>Cheng, Timmy</au><au>Tran, Uyen Phuong</au><au>Andrade, Rosa M</au><au>Brenner, Sara B T</au><au>Hwang, Grace</au><au>Cohn, Shara</au><au>Hirata, Ken</au><au>McKerrow, James H</au><au>Reed, Sharon L</au><au>Ferreira, Marcelo U.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Two key cathepsins, TgCPB and TgCPL, are targeted by the vinyl sulfone inhibitor K11777 in in vitro and in vivo models of toxoplasmosis</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2018-03-22</date><risdate>2018</risdate><volume>13</volume><issue>3</issue><spage>e0193982</spage><epage>e0193982</epage><pages>e0193982-e0193982</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Although toxoplasmosis is one of the most common parasitic infections worldwide, therapeutic options remain limited. Cathepsins, proteases that play key roles in the pathogenesis of toxoplasmosis and many other protozoan infections, are important potential therapeutic targets. Because both TgCPB and TgCPL play a role in T. gondii invasion, we evaluated the efficacy of the potent, irreversible vinyl sulfone inhibitor, K11777 (N-methyl-piperazine-Phe-homoPhe-vinylsulfone-phenyl). The inhibitor's toxicity and pharmacokinetic profile have been well-studied because of its in vitro and in vivo activity against a number of parasites. We found that it inhibited both TgCPB (EC50 = 114 nM) and TgCPL (EC50 = 71 nM) in vitro. K11777 also inhibited invasion of human fibroblasts by RH tachyzoites by 71% (p = 0.003) and intracellular replication by &gt;99% (p&lt;0.0001). In vivo, a single dose of K11777 led to 100% survival of chicken embryos in an model of acute toxoplasmosis (p = 0.015 Cox regression analysis). Therefore, K11777 shows promise as a novel therapeutic agent in the treatment of toxoplasmosis, and may prove to be a broadly effective anti-parasitic agent.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>29565998</pmid><doi>10.1371/journal.pone.0193982</doi><tpages>e0193982</tpages><orcidid>https://orcid.org/0000-0001-7615-9366</orcidid><oa>free_for_read</oa></addata></record>
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identifier ISSN: 1932-6203
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issn 1932-6203
1932-6203
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source Open Access: PubMed Central; Publicly Available Content Database
subjects Analysis
Animals
Antiparasitic agents
Antiparasitic Agents - pharmacology
Biocompatibility
Biology and Life Sciences
Cathepsins
Cathepsins - metabolism
Chemical compounds
Chickens
Development and progression
Dipeptides - pharmacology
Drug therapy
Embryos
Entamoeba histolytica
Fetuses
Fibroblasts
Fibroblasts - drug effects
Fibroblasts - metabolism
Health aspects
Humans
Infections
Infectious diseases
Inhibition
Inhibitors
Medicine
Medicine and Health Sciences
Parasites
Parasitic diseases
Pathogenesis
Pathology
Pharmacokinetics
Pharmacological research
Pharmacology
Pharmacy
Phenylalanine - analogs & derivatives
Physical Sciences
Physiological aspects
Piperazine
Piperazines
Proteins
Protozoa
Protozoan Proteins - metabolism
Regression analysis
Sulfones
Sulfones - antagonists & inhibitors
Tachyzoites
Therapeutic applications
Tosyl Compounds
Toxicity
Toxoplasma gondii
Toxoplasmosis
Toxoplasmosis - drug therapy
Toxoplasmosis - metabolism
Trypanosoma cruzi
Vinyl Compounds - pharmacology
Vinyl sulfone
title Two key cathepsins, TgCPB and TgCPL, are targeted by the vinyl sulfone inhibitor K11777 in in vitro and in vivo models of toxoplasmosis
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