Clinical and veterinary trypanocidal benzoxaboroles target CPSF3

Wall, Richard J.; Rico, Eva; Lukac, Iva; Zuccotto, Fabio; Elg, Sara; Gilbert, Ian H.; Freund, Yvonne R.; Alley, M.R.K.; Field, Mark C.; Wyllie, Susan; Horn, David

doi:10.1073/pnas.1807915115

Cited by 106 publications

(132 citation statements)

References 50 publications

Supporting

Mentioning

129

Contrasting

Unclassified

Order By: Relevance

“…Recent studies of AN7973 demonstrated that its trypanicidal activity results from inhibition of trypanosome mRNA processing 45 . Furthermore, related HAT and AAT lead compounds, also 6-amides like AN7973, target Cleavage and Polyadenylation Specific Factor 3 (CPSF3), an endonuclease that functions in mRNA processing 46 . It is known that other oxaboroles inhibit CPSF3 in Plasmodium falciparum 28 , and Cryptosporidium CPSF3 is greater than 40% identical to that of P. falciparum at the amino acid level.…”

Section: Discussionmentioning

confidence: 99%

Identification of a potent benzoxaborole drug candidate for treating cryptosporidiosis

Lunde¹,

Stebbins²,

Jumani³

et al. 2019

Nat Commun

View full text Add to dashboard Cite

Cryptosporidiosis is a leading cause of life-threatening diarrhea in young children and causes chronic diarrhea in AIDS patients, but the only approved treatment is ineffective in malnourished children and immunocompromised people. We here use a drug repositioning strategy and identify a promising anticryptosporidial drug candidate. Screening a library of benzoxaboroles comprised of analogs to four antiprotozoal chemical scaffolds under pre-clinical development for neglected tropical diseases for Cryptosporidium growth inhibitors identifies the 6-carboxamide benzoxaborole AN7973. AN7973 blocks intracellular parasite development, appears to be parasiticidal, and potently inhibits the two Cryptosporidium species most relevant to human health, C. parvum and C. hominis . It is efficacious in murine models of both acute and established infection, and in a neonatal dairy calf model of cryptosporidiosis. AN7973 also possesses favorable safety, stability, and PK parameters, and therefore, is an exciting drug candidate for treating cryptosporidiosis.

show abstract

Section: Discussionmentioning

confidence: 99%

Identification of a potent benzoxaborole drug candidate for treating cryptosporidiosis

Lunde¹,

Stebbins²,

Jumani³

et al. 2019

Nat Commun

View full text Add to dashboard Cite

show abstract

“…T. brucei and others in the class kinetoplastida primarily regulate gene expression post-transcriptionally based on transcript stability mediated by 5’ and 3’ UTRs (19). Thus, previous production of overexpression libraries, based on whole-genome fragmentation and cloning (20, 21), cannot ensure that individual ORFs are similarly activated upon induction. To mitigate these problems, we produced a T. brucei ORFeome using PCR amplification, which ensures the placement of each ORF under the same inducible gene regulation system.…”

Section: Resultsmentioning

confidence: 99%

ATrypanosoma bruceiORFeome-based Gain-of-Function Library reveals novel genes associated with melarsoprol resistance

Carter

Kim

Gomez

et al. 2019

Preprint

View full text Add to dashboard Cite

22 RR -Ribonucleotide reductase 39 40 41 42 43 44 45 46 ABSTRACT 47 Trypanosoma brucei is an early branching protozoan that causes Human and Animal 48 African Trypanosomiasis. Forward genetics approaches are powerful tools for 49 uncovering novel aspects of Trypanosomatid biology, pathogenesis, and therapeutic 50 approaches against trypanosomiasis. Here we have generated a T. brucei ORFeome 51 consisting of over 90% of the targeted genome and used it to make an inducible Gain-52 of-Function library for broadly applicable forward genetic screening. Using a critical drug 53 of last resort, melarsoprol, we conducted a proof of principle genetic screen. Hits arising 54 from this screen support the significance of trypanothione, a key player in redox 55 metabolism, as a target of melarsoprol and implicate novel proteins of the flagellum and 56 mitochondria in drug resistance. This study has produced two powerful new genetic 57 tools for kinetoplastida research, which are expected to promote major advances in 58 kinetoplastida biology and therapeutic development in the years to come. 59 60 61 62 63 64 65 66 67 68 69 associated with organism specific aspects of parasitism, such as surface antigen 85 variation, leaving many biological functions highly conserved among kinetoplastida 86 parasites (3). Trypanosomatids share essential subcellular structures, such as the 87 flagellum, glycosomes (specialized organelles of glycolysis), and the kinetoplast (a 88 network of mitochondrial DNA). While reverse genetics based on well-established 89 models can promote discrete advances, forward genetics approaches have the potential 90 to uncover important aspects of kinetoplastida biology shared among orthologous 91 genes. 92 T. brucei, the causative agent of Human African trypanosomiasis (HAT), has 93 traditionally been the most genetically tractable of the Trypanosomatid parasites. 94Discoveries made in T. brucei have provided critical understanding to the biology of 95 other kinetoplastida as well as providing insights into eukaryotic evolution (4-7) and 96 uncovered broadly significant biological processes, such as GPI-anchors and 97

show abstract

“…Over-expression of the gene yielded a notable loss of activity [96]. Elegant experiments using a gene over-expression library, followed by a selection of clones over-expressing genes yielding reduced sensitivity to acoziborole itself, also identified CPSF3 [97], and over-expression confirmed loss of sensitivity, pointing to CPSF3 as a target, if not the exclusive target, of these compounds in trypanosomes.…”

Section: Acoziborole: Mode Of Action and Resistance Riskmentioning

confidence: 93%

New Drugs for Human African Trypanosomiasis: A Twenty First Century Success Story

et al. 2020

View full text Add to dashboard Cite

The twentieth century ended with human African trypanosomiasis (HAT) epidemics raging across many parts of Africa. Resistance to existing drugs was emerging, and many programs aiming to contain the disease had ground to a halt, given previous success against HAT and the competing priorities associated with other medical crises ravaging the continent. A series of dedicated interventions and the introduction of innovative routes to develop drugs, involving Product Development Partnerships, has led to a dramatic turnaround in the fight against HAT caused by Trypanosoma brucei gambiense. The World Health Organization have been able to optimize the use of existing tools to monitor and intervene in the disease. A promising new oral medication for stage 1 HAT, pafuramidine maleate, ultimately failed due to unforeseen toxicity issues. However, the clinical trials for this compound demonstrated the possibility of conducting such trials in the resource-poor settings of rural Africa. The Drugs for Neglected Disease initiative (DNDi), founded in 2003, has developed the first all oral therapy for both stage 1 and stage 2 HAT in fexinidazole. DNDi has also brought forward another oral therapy, acoziborole, potentially capable of curing both stage 1 and stage 2 disease in a single dosing. In this review article, we describe the remarkable successes in combating HAT through the twenty first century, bringing the prospect of the elimination of this disease into sight.

show abstract

Clinical and veterinary trypanocidal benzoxaboroles target CPSF3

Cited by 106 publications

References 50 publications

Identification of a potent benzoxaborole drug candidate for treating cryptosporidiosis

Identification of a potent benzoxaborole drug candidate for treating cryptosporidiosis

ATrypanosoma bruceiORFeome-based Gain-of-Function Library reveals novel genes associated with melarsoprol resistance

New Drugs for Human African Trypanosomiasis: A Twenty First Century Success Story

Contact Info

Product

Resources

About