Melarsoprol Resistance in African Trypanosomiasis

Fairlamb, Alan H.; Horn, David

doi:10.1016/j.pt.2018.04.002

Cited by 109 publications

(106 citation statements)

References 94 publications

(117 reference statements)

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“…Approximately 70 million people live in at‐risk areas worldwide, and although 1,447 cases were reported in 2017 (World Health Organization, http://www.who.int), it is estimated that many more across Africa are infected with HAT (Franco, Simarro, Diarra, & Jannin, ). HAT is inevitably fatal without therapeutic intervention, but that can be inefficient due to parasite resistance (Barrett, Boykin, Brun, & Tidwell, ) and marked host toxicity (Fairlamb & Horn, ), and there is a critical need for new drugs to control spread of the disease and associated mortality. Toward this end, a better understanding of the basic biology of the parasite is essential, particularly of processes that may be amenable to therapeutics.…”

Section: Introductionmentioning

confidence: 99%

Processing and targeting of cathepsin L (TbCatL) to the lysosome inTrypanosoma brucei

Koeller

Bangs

2019

Cellular Microbiology

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Cathepsin L (TbCatL) is an essential lysosomal thiol protease in African trypanosomes. TbCatL is synthesized as two precursor forms (P/X) that are activated to mature form (M) with the removal of the prodomain upon arrival in the lysosome. We examine TbCatL trafficking in a novel system: truncated TbCatL reporter without the C‐terminal domain (CTD; TbCatL∆) ectopically expressed in an RNA interference (RNAi) cell line targeting the CTD/3′ untranslated region (UTR) of endogenous mRNA. TbCatL∆ is synthesized as P′/X′/M′ species, localizes to the lysosome, and rescues the lethal TbCatL RNAi phenotype. Inactive TbCatLΔ:C150A is only processed to M′ in the presence of endogenous TbCatL indicating trans‐auto‐catalytic activation. X′ is formed with active endoplasmic reticulum (ER)‐retained TbCatLΔ:MDDL, but not with TbCatLΔ:C150A, indicating stochastic generation in the ER by cis‐auto‐cleavage within the prodomain of newly synthesized P′. Modelling the TbCatL prodomain on the human CatL structure suggests three solvent accessible features that could contain post‐Golgi targeting signals: the N‐terminus, the helix 1/turn 1 junction, and a separate turn (T3). We demonstrate that the critical motif for lysosomal targeting is an asparagine‐proline dipeptide in T3 that is strictly conserved in all Kinetoplastida. These findings show novel insights on the maturation of TbCatL, which is a critical virulence factor in mammalian infection.

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Section: Introductionmentioning

confidence: 99%

Processing and targeting of cathepsin L (TbCatL) to the lysosome inTrypanosoma brucei

Koeller

Bangs

2019

Cellular Microbiology

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“…Unfortunately, all of the five currently approved drugs (suramin, melarsoprol, pentamidine, eflornithine and nifurtimox) are unsatisfactory owing to various degrees of toxicity, low efficacies and the necessity for parenteral administration. Furthermore, drug resistance is a growing problem, especially in the case of the arsenical melarsoprol . As a consequence, the search for new and advanced HAT therapeutics is urgent…”

Section: Figurementioning

confidence: 99%

Bioinspired Design of Lysolytic Triterpenoid–Peptide Conjugates that Kill African Trypanosomes

et al. 2019

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Humans have evolved a natural immunity against Trypanosoma brucei infections, which is executed by two serum (lipo)protein complexes known as trypanolytic factors (TLF). The active TLF ingredient is the primate‐specific apolipoprotein L1 (APOL1). The protein has a pore‐forming activity that kills parasites by lysosomal and mitochondrial membrane fenestration. Of the many trypanosome subspecies, only two are able to counteract the activity of APOL1; this illustrates its evolutionarily optimized design and trypanocidal potency. Herein, we ask whether a synthetic (syn) TLF can be synthesized by using the design principles of the natural TLF complexes but with different chemical building blocks. We demonstrate the stepwise development of triterpenoid–peptide conjugates, in which the triterpenoids act as a cell‐binding, uptake and lysosomal‐transport modules and the synthetic peptide GALA acts as a pH‐sensitive, pore‐forming lysolytic toxin. As designed, the conjugate kills infective‐stage African trypanosomes through lysosomal lysis thus demonstrating a proof‐of‐principle for the bioinspired, forward‐design of a synTLF.

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“…Although not listed among essential transporters for the parasite, they can indeed modify the distribution of the drugs in the cell and in its organelles, either allowing or preventing the inhibitors to reach their targets. Moreover, as for other drugs, transporters might be involved in resistance mechanisms, a possibility that should be taken into account for the development of new successful therapies…”

Section: Transportersmentioning

confidence: 99%

Folates in Trypanosoma brucei: Achievements and Opportunities

et al. 2018

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Trypanosoma brucei is the agent of human African trypanosomiasis (HAT), a neglected disease that threatens the lives of 65 million people in sub-Saharan Africa every year. Unfortunately, available therapies are unsatisfactory, due primarily to safety issues and development of drug resistance. Over the last decades significant effort has been made in the discovery of new potential anti-HAT agents, with help from the World Health Organization (WHO) and private-public partnerships such as the Drugs for Neglected Diseases Initiative (DNDi). Whereas antifolates have been a valuable source of drugs against bacterial infections and malaria, compounds effective against T. brucei have not yet been identified. Considering the relatively simple folate metabolic pathway in T. brucei, along with results obtained in this research field so far, we believe that further investigations might lead to effective chemotherapeutic agents. Herein we present a selection of the more promising results obtained so far in this field, underlining the opportunities that could lead to successful therapeutic approaches in the future.

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Melarsoprol Resistance in African Trypanosomiasis

Cited by 109 publications

References 94 publications

Processing and targeting of cathepsin L (TbCatL) to the lysosome inTrypanosoma brucei

Processing and targeting of cathepsin L (TbCatL) to the lysosome inTrypanosoma brucei

Bioinspired Design of Lysolytic Triterpenoid–Peptide Conjugates that Kill African Trypanosomes

Folates in Trypanosoma brucei: Achievements and Opportunities

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