A Brief Review of Drug Discovery Research for Human African Trypanosomiasis

Cullen, Danica R.; Mocerino, Mauro

doi:10.2174/0929867324666170120160034

Cited by 22 publications

(17 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Eflornithine is less toxic than melarsoprol, however it is difficult to administer and more expensive. Drug administration requires rigorous administration schemes through slow intravenous infusion over several days [28].…”

Section: Current Drug Target Screening For Human African Trypanosomentioning

confidence: 99%

Trypanosoma brucei Interaction with Host: Mechanism of VSG Release as Target for Drug Discovery for African Trypanosomiasis

Moreno

Temporão

Torres

et al. 2019

IJMS

View full text Add to dashboard Cite

The protozoan Trypanosoma brucei, responsible for animal and human trypanosomiasis, has a family of major surface proteases (MSPs) and phospholipase-C (PLC), both involved in some mechanisms of virulence during mammalian infections. During parasitism in the mammalian host, this protozoan is exclusively extracellular and presents a robust mechanism of antigenic variation that allows the persistence of infection. There has been incredible progress in our understanding of how variable surface glycoproteins (VSGs) are organised and expressed, and how expression is switched, particularly through recombination. The objective of this manuscript is to create a reflection about the mechanisms of antigenic variation in T. brucei, more specifically, in the process of variable surface glycoprotein (VSG) release. We firstly explore the mechanism of VSG release as a potential pathway and target for the development of anti-T. brucei drugs.

show abstract

Section: Current Drug Target Screening For Human African Trypanosomentioning

confidence: 99%

Trypanosoma brucei Interaction with Host: Mechanism of VSG Release as Target for Drug Discovery for African Trypanosomiasis

Moreno

Temporão

Torres

et al. 2019

IJMS

View full text Add to dashboard Cite

show abstract

“…In addition, BSF endocytosis is clathrin dependent and 10-fold faster than in PCF ( Morgan et al, 2001 ; Pal et al, 2002 ). Drugs currently used to treat HAT have limited efficacy, they are toxic and/or are hampered by the continual appearance of resistance and, therefore, there is an urgent need for new medications ( Cullen and Mocerino, 2017 ). Ideally, to avoid cross-resistance phenomena, any new drugs must have a different uptake mechanism and/or action than those in use today.…”

Section: Introductionmentioning

confidence: 99%

Autophagic-related cell death of Trypanosoma brucei induced by bacteriocin AS-48

Martínez‐García

Bart

Campos‐Salinas

et al. 2018

International Journal for Parasitology: Drugs and Drug Resistan

View full text Add to dashboard Cite

The parasitic protozoan Trypanosoma brucei is the causative agent of human African trypanosomiasis (sleeping sickness) and nagana. Current drug therapies have limited efficacy, high toxicity and/or are continually hampered by the appearance of resistance. Antimicrobial peptides have recently attracted attention as potential parasiticidal compounds. Here, we explore circular bacteriocin AS-48's ability to kill clinically relevant bloodstream forms of T. brucei gambiense, T. brucei rhodesiense and T. brucei brucei. AS-48 exhibited excellent anti-trypanosomal activity in vitro (EC50 = 1–3 nM) against the three T. brucei subspecies, but it was innocuous to human cells at 104-fold higher concentrations. In contrast to its antibacterial action, AS-48 does not kill the parasite through plasma membrane permeabilization but by targeting intracellular compartments. This was evidenced by the fact that vital dye internalization-prohibiting concentrations of AS-48 could kill the parasite at 37 °C but not at 4 °C. Furthermore, AS-48 interacted with the surface of the parasite, at least in part via VSG, its uptake was temperature-dependent and clathrin-depleted cells were less permissive to the action of AS-48. The bacteriocin also caused the appearance of myelin-like structures and double-membrane autophagic vacuoles. These changes in the parasite's ultrastructure were confirmed by fluorescence microscopy as AS-48 induced the production of EGFP-ATG8.2-labeled autophagosomes. Collectively, these results indicate AS-48 kills the parasite through a mechanism involving clathrin-mediated endocytosis of VSG-bound AS-48 and the induction of autophagic-like cell death. As AS-48 has greater in vitro activity than the drugs currently used to treat T. brucei infection and does not present any signs of toxicity in mammalian cells, it could be an attractive lead compound for the treatment of sleeping sickness and nagana.

show abstract

“…Control of these diseases is difficult, as the parasites have complex life cycles involving insect vectors. Current treatments for HAT ( 3 ), Chagas’ disease ( 4 ), and leishmaniasis ( 5 ) are highly toxic, the treatment regimens are difficult to implement, and the availability of some of them is limited. Emerging resistance and limited efficacy of available drugs emphasize the need for the development of new drugs with novel targets.…”

Section: Introductionmentioning

confidence: 99%

Structural Characterization of Acidic M17 Leucine Aminopeptidases from the TriTryps and Evaluation of Their Role in Nutrient Starvation in Trypanosoma brucei

Timm

Valente

García-Caballero

et al. 2017

mSphere

View full text Add to dashboard Cite

Leucine aminopeptidases (LAPs) catalyze the hydrolysis of the N-terminal amino acid of peptides and are considered potential drug targets. They are involved in multiple functions ranging from host cell invasion and provision of essential amino acids to site-specific homologous recombination and transcription regulation. In kinetoplastid parasites, there are at least three distinct LAPs. The availability of the crystal structures provides important information for drug design. Here we report the structure of the acidic LAPs from three kinetoplastids in complex with different inhibitors and explore their role in Trypanosoma brucei survival under various nutrient conditions. Importantly, the acidic LAP is dispensable for growth both in vitro and in vivo, an observation that questions its use as a specific drug target. While LAP-A is not essential, leucine depletion and subcellular localization studies performed under starvation conditions suggest a possible function of LAP-A in the response to nutrient restriction.

show abstract

A Brief Review of Drug Discovery Research for Human African Trypanosomiasis

Cited by 22 publications

References 0 publications

Trypanosoma brucei Interaction with Host: Mechanism of VSG Release as Target for Drug Discovery for African Trypanosomiasis

Trypanosoma brucei Interaction with Host: Mechanism of VSG Release as Target for Drug Discovery for African Trypanosomiasis

Autophagic-related cell death of Trypanosoma brucei induced by bacteriocin AS-48

Structural Characterization of Acidic M17 Leucine Aminopeptidases from the TriTryps and Evaluation of Their Role in Nutrient Starvation in Trypanosoma brucei

Contact Info

Product

Resources

About