Publications by authors named "Conor R Caffrey"

The proteasome is essential for eukaryotic cell proteostasis, and inhibitors of the 20S proteasome are progressing preclinically and clinically as antiparasitics. We screened, the causative agent of human and animal African trypanosomiasis, with a set of 27 carmaphycin B analogs, irreversible epoxyketone inhibitors that were originally developed to inhibit the20S (Pf20S). The structure-activity relationship was distinct from that of the human c20S antitarget by the acceptance of d-amino acids at the P3 position of the peptidyl backbone to yield compounds with greatly decreased toxicity to human cells.

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Article Synopsis
  • Trichomonas vaginalis (Tv) is a protozoan parasite that causes trichomoniasis, the most prevalent non-viral sexually transmitted infection globally, but current treatment options are limited and facing resistance issues.
  • Researchers are targeting the proteasome, a key enzyme complex in eukaryotes, to develop new treatments by isolating the enzyme and identifying specific inhibitors for its three catalytic subunits (β1, β2, β5).
  • By creating specialized substrates for each subunit and screening a library of inhibitors, the study found that targeting the Tv β5 subunit is particularly effective in killing the parasite, which may lead to improved drug development strategies against trichomoniasis.
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Human schistosomiasis, caused by the trematode, is a neglected parasitic disease affecting over 250 million people worldwide. There is no vaccine, and the single available drug is threatened by drug resistance. This study presents a computational approach to designing multiepitope vaccines (MEVs) targeting the cercarial (CMEV) and schistosomular (SMEV) stages of schistosomes, and identifies potential schistosomicidal compounds from the Medicine for Malaria Ventures (MMV) and SuperNatural Database (SND) libraries.

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The proteasome is a proteolytically active molecular machine comprising many different protein subunits. It is essential for growth and survival in eukaryotic cells and has long been considered a drug target. Here, we summarize the biology of the proteasome, the early research relating to the development of specific proteasome inhibitors (PIs) for treatment of various cancers, and their translation and eventual evolution as exciting therapies for parasitic diseases.

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The 20S proteasome is a multimeric protease complex that is essential for proteostasis in the cell. Small molecule proteasome inhibitors are approved drugs for various cancers and are advancing clinically as antiparasitics. Although tools and technologies to study the 20S proteasome have advanced, only one probe is commercially available to image proteasome activity.

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Schistosomiasis is a neglected disease of poverty that affects over 200 million people worldwide and relies on a single drug for therapy. The cathepsin B1 cysteine protease (SmCB1) of has been investigated as a potential target. Here, a structure-based pharmacophore virtual screening (VS) approach was used on a data set of approved drugs to identify potential antischistosomal agents targeting SmCB1.

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Kavaratamide A (), a new linear lipodepsipeptide possessing an unusual isopropyl--methylpyrrolinone moiety, was discovered from the tropical marine filamentous cyanobacterium collected from Kavaratti, India. A comparative chemogeographic analysis of . collected from six different geographical regions led to the prioritized isolation of this metabolite from India as distinctive among our data sets.

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Schistosomiasis, caused by a parasitic blood fluke of the genus is a global health problem for which new chemotherapeutic options are needed. We explored the scaffold of gallinamide A, a natural peptidic metabolite of marine cyanobacteria that has previously been shown to inhibit cathepsin L-type proteases. We screened a library of 19 synthetic gallinamide A analogs and identified nanomolar inhibitors of the cathepsin B-type protease SmCB1, which is a drug target for the treatment of schistosomiasis mansoni.

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Article Synopsis
  • * Researchers are exploring new drug targets, specifically the 20S proteasome, which has proven successful for other parasitic infections, to find more effective treatments against schistosomiasis.
  • * By using advanced techniques like Multiplex Substrate Profiling by Mass Spectrometry, the team created optimized substrates that better measure the activity of the schistosome proteasome and found that their research could potentially benefit multiple schistosome species, leading to more efficient drug development.
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Nagana and Human African Trypanosomiasis (HAT), caused by (sub)species of Trypanosoma, are diseases that impede human and animal health, and economic growth in Africa. The few drugs available have drawbacks including suboptimal efficacy, adverse effects, drug resistance, and difficult routes of administration. New drugs are needed.

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Studies have shown that depending on the substitution pattern, microtubule (MT)-targeting 1,2,4-triazolo[1,5-a]pyrimidines (TPDs) can produce different cellular responses in mammalian cells that may be due to these compounds interacting with distinct binding sites within the MT structure. Selected TPDs are also potently bioactive against the causative agent of human African trypanosomiasis, Trypanosoma brucei, both in vitro and in vivo. So far, however, there has been no direct evidence of tubulin engagement by these TPDs in T.

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The dissemination of protozoan and metazoan parasites through host tissues is hindered by cellular barriers, dense extracellular matrices, and fluid forces in the bloodstream. To overcome these diverse biophysical impediments, parasites implement versatile migratory strategies. Parasite-exerted mechanical forces and upregulation of the host's cellular contractile machinery are the motors for these strategies, and these are comparably better characterized for protozoa than for helminths.

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The covalent reversible modification of proteins is a validated strategy for the development of probes and candidate therapeutics. However, the covalent reversible targeting of noncatalytic lysines is particularly challenging. Herein, we characterize the 2-hydroxy-1-naphthaldehyde (HNA) fragment as a targeted covalent reversible ligand of a noncatalytic lysine (Lys) of the Krev interaction trapped 1 (KRIT1) protein.

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Schistosomiasis is a neglected tropical disease caused by a parasitic, trematode blood fluke of the genus Schistosoma. With 20 million people infected, mostly due to Schistosoma haematobium, Nigeria has the highest burden of schistosomiasis in the world. We review the status of human schistosomiasis in Nigeria regarding its distribution, prevalence, diagnosis, prevention, orthodox and traditional treatments, as well as snail control strategies.

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Tubulin and microtubules (MTs) are potential protein targets to treat parasitic infections and our previous studies have shown that the triazolopyrimidine (TPD) class of MT-active compounds hold promise as antitrypanosomal agents. MT-targeting TPDs include structurally related but functionally diverse congeners that interact with mammalian tubulin at either one or two distinct interfacial binding sites; namely, the seventh and vinca sites, which are found within or between α,β-tubulin heterodimers, respectively. Evaluation of the activity of 123 TPD congeners against cultured Trypanosoma brucei enabled a robust quantitative structure-activity relationship (QSAR) model and the prioritization of two congeners for in vivo pharmacokinetics (PK), tolerability and efficacy studies.

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Brazil has a megadiversity that includes marine species that are distributed along 800 km of shoreline. This biodiversity status holds promising biotechnological potential. Marine organisms are important sources of novel chemical species, with applications in the pharmaceutical, cosmetic, chemical, and nutraceutical fields.

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The development of small-molecule inhibitors or stabilizers of selected protein-protein interactions (PPIs) of interest holds considerable promise for the development of research tools as well as candidate therapeutics. In this context, the covalent modification of selected residues within the target protein has emerged as a promising mechanism of action to obtain small-molecule modulators of PPIs with appropriate selectivity and duration of action. Different covalent labeling strategies are now available that can potentially allow for a rational, ground-up discovery and optimization of ligands as PPI inhibitors or stabilizers.

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Article Synopsis
  • * The meeting highlighted that while PZQ is the only available treatment for all schistosomiasis species, it often fails to completely eliminate the infection, particularly in juvenile worms, and may face resistance issues.
  • * Experts discussed the essential criteria for developing new anti-schistosomal medications and potential drug discovery pathways to improve treatment options for this public health concern.
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The protozoan parasite, (Tv) causes trichomoniasis, the most common, non-viral, sexually transmitted infection in the world. Only two closely related drugs are approved for its treatment. The accelerating emergence of resistance to these drugs and lack of alternative treatment options poses an increasing threat to public health.

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Tubulin and microtubules (MTs) are potential protein targets to treat parasitic infections and our previous studies have shown that the triazolopyrimidine (TPD) class of MT- active compounds hold promise as antitrypanosomal agents. MT-targeting TPDs include structurally related but functionally diverse congeners that interact with mammalian tubulin at either one or two distinct interfacial binding sites; namely, the seventh and vinca sites, which are found within or between α,β-tubulin heterodimers, respectively. Evaluation of the activity of 123 TPD congeners against cultured enabled a robust quantitative structure-activity relationship (QSAR) model and the prioritization of two congeners for pharmacokinetics (PK), tolerability and efficacy studies.

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For the Schistosoma mansoni flatworm pathogen, we report a structure-activity relationship of 25 derivatives of the N-phenylbenzamide compound, 1 (MMV687807), a Medicines for Malaria Venture compound for which bioactivity was originally identified in 2018. Synthesized compounds were cross-screened against the HEK 293 mammalian cells. Compounds 9 and 11 were identified as fast-acting schistosomicidal compounds whereby adult worm integrity was severely compromised within 1 h.

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Trypanosoma brucei is a protozoan parasite that causes Human African Trypanosomiasis (HAT), a neglected tropical disease (NTD) that is endemic in 36 countries in sub-Saharan Africa. Only a handful drugs are available for treatment, and these have limitations, including toxicity and drug resistance. Using the natural product, curcumin, as a starting point, several curcuminoids and related analogs were evaluated against bloodstream forms of T.

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Metals have been used in medicine since ancient times for the treatment of different ailments with various elements such as iron, gold and arsenic. Metal complexes have also been reported to show antibiotic and antiparasitic activity. In this context, we tested the antiparasitic potential of 10 organotin (IV) derivatives from 4-(4-methoxyphenylamino)-4 oxobutanoic acid (MS26) against seven eukaryotic pathogens of medical importance: , , , , , and .

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Microtubule (MT)-stabilizing 1,2,4-triazolo[1,5-]pyrimidines (TPDs) hold promise as candidate therapeutics for Alzheimer's disease (AD) and other neurodegenerative conditions. However, depending on the choice of substituents around the TPD core, these compounds can elicit markedly different cellular phenotypes that likely arise from the interaction of TPD congeners with either one or two spatially distinct binding sites within tubulin heterodimers (, the seventh site and the vinca site). In the present study, we report the design, synthesis, and evaluation of a series of new TPD congeners, as well as matched molecular pair analyses and computational studies, that further elucidate the structure-activity relationships of MT-active TPDs.

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