Year-end Sale % OFF 
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 >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.
Highlights
Toxoplasma gondii is an intracellular protozoan parasite recognized as a pathogen more than 100 years ago
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-PhehomoPhe-vinylsulfone-phenyl)
We show that K11777 significantly blocks invasion and multiplication of T. gondii in vitro, and that a single dose dramatically prevents mortality in a chick model of toxoplasmosis
Summary
Toxoplasma gondii is an intracellular protozoan parasite recognized as a pathogen more than 100 years ago. Humans acquire the parasite mainly through ingestion of contaminated undercooked meat, food or water contaminated with feline feces, vertical transmission from mother to fetus, or through blood transfusions or organ transplants [1]. An estimated 22.5% of the population 12 years and older or 60,000,000 people in the US have been infected with toxoplasmosis, and the seroprevalence is markedly higher in developing countries [2,3]. Primary infection of the fetus (approximately 1 in 1000 live births in the US) can cause devastating and even fatal disease [4,5]. Reactivation of latent infection in immunosuppressed individuals, AIDS patients, can manifest as Toxoplasma encephalitis, a uniformly fatal condition if left untreated [2]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
