Nicotinamide Inhibits the Lysosomal Cathepsin b-like Protease and Kills African Trypanosomes

Unciti-Broceta, Juan D.; Maceira, José; Morales, Sonia; García‐Pérez, Angélica; Muñóz-Torres, Manuel; García‐Salcedo, José A.

doi:10.1074/jbc.m112.449207

Cited by 29 publications

(21 citation statements)

References 36 publications

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“…Contrary to previous studies [179], we could not observe any antiparasitic activity of nicotinamide against T. cruzi amastigotes for up to a concentration of 2 mM. Several studies report the activity of nicotinamide against parasitic protozoa [180][181][182], but to our knowledge, none clearly establishes a relation between antiparasitic activity and sirtuin inhibition.…”

Section: Potential Of Trypanosoma Cruzi Sirtuins As Targets For Infeccontrasting

confidence: 99%

Silent Information Regulator 2 from Trypanosoma cruzi Is a Potential Target to Infection Control

Gaspar¹,

Smith²,

Moretti³

et al. 2018

Chagas Disease - Basic Investigations and Challenges

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Human trypanosomiasis is a neglected tropical disease caused by protozoan parasites of the genus Trypanosoma. Trypanosoma brucei is responsible for sleeping sickness, also called African trypanosomiasis, while Trypanosoma cruzi causes Chagas disease, or American trypanosomiasis. Together, these diseases are responsible for significant mortality, morbidity and lost productivity in the endemic regions. There are no vaccines and treatments rely on drugs with limited efficacy, high cost, serious side effects and long administration periods. Since these diseases affect mostly the poor, there is no economic interest in the development of new drugs by pharmaceutical companies, and hopes for new treatments rely on public initiatives, public-private partnerships or philanthropic programs. The first step in the discovery of new drugs involves the identification of active molecules as starting points for further development, by either employing whole cells or by specific molecular target screenings. Research efforts undertaken by the authors' groups have focused on exploiting both strategies in the search for new molecules for trypanosomiasis drug discovery. In this chapter, we focus on Chagas disease and the recently uncovered potential of using sirtuins as targets for infection control.

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Section: Potential Of Trypanosoma Cruzi Sirtuins As Targets For Infeccontrasting

confidence: 99%

Silent Information Regulator 2 from Trypanosoma cruzi Is a Potential Target to Infection Control

Gaspar¹,

Smith²,

Moretti³

et al. 2018

Chagas Disease - Basic Investigations and Challenges

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“…Cell viability was evaluated as previously described [46]. Eleven dilution points were tested, ranging from 680 μM to 165 pM in pentamidine concentration.…”

Section: In Vitro Viability Assaymentioning

confidence: 99%

Nanobody conjugated PLGA nanoparticles for active targeting of African Trypanosomiasis

Arias

Unciti-Broceta

Maceira

et al. 2015

Journal of Controlled Release

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Targeted delivery of therapeutics is an alternative approach for the selective treatment of infectious diseases. The surface of African trypanosomes, the causative agents of African trypanosomiasis, is covered by a surface coat consisting of a single variant surface glycoprotein, termed VSG. This coat is recycled by endocytosis at a very high speed, making the trypanosome surface an excellent target for the delivery of trypanocidal drugs. Here, we report the design of a drug nanocarrier based on poly ethylen glycol (PEG) covalently attached (PEGylated) to poly(D,L-lactide-co-glycolide acid) (PLGA) to generate PEGylated PLGA nanoparticles. This nanocarrier was coupled to a single domain heavy chain antibody fragment (nanobody) that specifically recognizes the surface of the protozoan pathogen Trypanosoma brucei. Nanoparticles were loaded with pentamidine, the first-line drug for T. b. gambiense acute infection. An in vitro effectiveness assay showed a 7-fold decrease in the half-inhibitory concentration (IC50) of the formulation relative to free drug. Furthermore, in vivo therapy using a murine model of African trypanosomiasis demonstrated that the formulation cured all infected mice at a 10-fold lower dose than the minimal full curative dose of free pentamidine and 60% of mice at a 100-fold lower dose. This nanocarrier has been designed with components approved for use in humans and loaded with a drug that is currently in use to treat the disease. Moreover, this flexible nanobody-based system can be adapted to load any compound, opening a range of new potential therapies with application to other diseases.

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“…Trypanotoxicity was determined using an adapted version of the resazurin sodium salt method [ 50 ]. Briefly, exponentially growing parasites (monomorphic T .…”

Section: Methodsmentioning

confidence: 99%

Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis

et al. 2015

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African trypanosomiasis is a deadly neglected disease caused by the extracellular parasite Trypanosoma brucei. Current therapies are characterized by high drug toxicity and increasing drug resistance mainly associated with loss-of-function mutations in the transporters involved in drug import. The introduction of new antiparasitic drugs into therapeutic use is a slow and expensive process. In contrast, specific targeting of existing drugs could represent a more rapid and cost-effective approach for neglected disease treatment, impacting through reduced systemic toxicity and circumventing resistance acquired through impaired compound uptake. We have generated nanoparticles of chitosan loaded with the trypanocidal drug pentamidine and coated by a single domain nanobody that specifically targets the surface of African trypanosomes. Once loaded into this nanocarrier, pentamidine enters trypanosomes through endocytosis instead of via classical cell surface transporters. The curative dose of pentamidine-loaded nanobody-chitosan nanoparticles was 100-fold lower than pentamidine alone in a murine model of acute African trypanosomiasis. Crucially, this new formulation displayed undiminished in vitro and in vivo activity against a trypanosome cell line resistant to pentamidine as a result of mutations in the surface transporter aquaglyceroporin 2. We conclude that this new drug delivery system increases drug efficacy and has the ability to overcome resistance to some anti-protozoal drugs.

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Nicotinamide Inhibits the Lysosomal Cathepsin b-like Protease and Kills African Trypanosomes

Cited by 29 publications

References 36 publications

Silent Information Regulator 2 from Trypanosoma cruzi Is a Potential Target to Infection Control

Silent Information Regulator 2 from Trypanosoma cruzi Is a Potential Target to Infection Control

Nanobody conjugated PLGA nanoparticles for active targeting of African Trypanosomiasis

Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis

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