Two key cathepsins, TgCPB and TgCPL, are targeted by the vinyl sulfone inhibitor K11777 in in vitro and in vivo models of toxoplasmosis Article Swipe
Juan D. Chaparro
,
Timmy Cheng
,
Uyen Phuong Tran
,
Rosa M. Andrade
,
S. Brenner
,
Grace Hwang
,
Shara Cohn
,
Ken Hirata
,
James H. McKerrow
,
Sharon L. Reed
·
YOU?
·
· 2018
· Open Access
·
· DOI: https://doi.org/10.1371/journal.pone.0193982
YOU?
·
· 2018
· Open Access
·
· DOI: https://doi.org/10.1371/journal.pone.0193982
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<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.
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Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1371/journal.pone.0193982
- https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0193982&type=printable
- OA Status
- gold
- Cited By
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- References
- 36
- Related Works
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- OpenAlex ID
- https://openalex.org/W2792087926
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W2792087926Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1371/journal.pone.0193982Digital Object Identifier
- Title
-
Two key cathepsins, TgCPB and TgCPL, are targeted by the vinyl sulfone inhibitor K11777 in in vitro and in vivo models of toxoplasmosisWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2018Year of publication
- Publication date
-
2018-03-22Full publication date if available
- Authors
-
Juan D. Chaparro, Timmy Cheng, Uyen Phuong Tran, Rosa M. Andrade, S. Brenner, Grace Hwang, Shara Cohn, Ken Hirata, James H. McKerrow, Sharon L. ReedList of authors in order
- Landing page
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https://doi.org/10.1371/journal.pone.0193982Publisher landing page
- PDF URL
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https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0193982&type=printableDirect link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
- OA URL
-
https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0193982&type=printableDirect OA link when available
- Concepts
-
In vivo, Toxoplasmosis, Toxoplasma gondii, In vitro, Pharmacology, Biology, Cathepsin, Microbiology, Immunology, Biochemistry, Enzyme, Antibody, BiotechnologyTop concepts (fields/topics) attached by OpenAlex
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-
20Total citation count in OpenAlex
- Citations by year (recent)
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2025: 2, 2024: 4, 2023: 2, 2022: 2, 2020: 4Per-year citation counts (last 5 years)
- References (count)
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36Number of works referenced by this work
- Related works (count)
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10Other works algorithmically related by OpenAlex
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| referenced_works | https://openalex.org/W2097659338, https://openalex.org/W2028314170, https://openalex.org/W2107086088, https://openalex.org/W161548343, https://openalex.org/W2084222903, https://openalex.org/W2021293112, https://openalex.org/W2142788740, https://openalex.org/W2011640853, https://openalex.org/W2157017502, https://openalex.org/W2150615185, https://openalex.org/W1973578597, https://openalex.org/W2089838208, https://openalex.org/W2027862731, https://openalex.org/W2097032189, https://openalex.org/W2093020034, https://openalex.org/W2118831024, https://openalex.org/W2172177549, https://openalex.org/W1975302732, https://openalex.org/W2138865920, https://openalex.org/W2154568785, https://openalex.org/W2169156755, https://openalex.org/W1973796287, https://openalex.org/W1537498478, https://openalex.org/W2093630829, https://openalex.org/W2031723508, https://openalex.org/W34195167, https://openalex.org/W2150558096, https://openalex.org/W1982187630, https://openalex.org/W2166180305, https://openalex.org/W2075766387, https://openalex.org/W2088245563, https://openalex.org/W2027829853, https://openalex.org/W2136903689, https://openalex.org/W2534610127, https://openalex.org/W2677736497, https://openalex.org/W2000661169 |
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| corresponding_author_ids | https://openalex.org/A5089001551, https://openalex.org/A5002359982, https://openalex.org/A5053601743, https://openalex.org/A5072334490, https://openalex.org/A5082146151, https://openalex.org/A5033544787, https://openalex.org/A5038403538, https://openalex.org/A5050757556, https://openalex.org/A5101029755, https://openalex.org/A5050856602 |
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