Publications by authors named "Voorhis W"
Cryptosporidium parvum is a protozoan parasite that causes severe diarrheal illness in children and each year nearly 50,000 children under age 5 die due to the disease. Despite tremendous research efforts, there remains a lack of effective therapies and vaccines. Novel inhibitors against N-myristoyltransferase of C.
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- Drug development for congenital toxoplasmosis is challenging due to high adverse effects and poor efficacy of first-line therapies; bumped kinase inhibitors (BKIs) like BKI-1748 may offer a new treatment option.
- In a study involving 19 pregnant sheep, those treated with BKI-1748 after infection showed lower fever and immunological responses compared to untreated counterparts.
- The treated group had a higher percentage of healthy lambs at delivery and showed no evidence of congenital transmission of the parasite, unlike the untreated group where parasite DNA was detectable.
Griselimycin, a cyclic depsidecapeptide produced by Streptomyces griseus, is a promising lead inhibitor of the sliding clamp component of bacterial DNA polymerases (β-subunit of Escherichia coli DNA pol III). It was previously shown to inhibit the Mycobacterium tuberculosis β-clamp with remarkably high affinity and selectivity - the peptide lacks any interaction with the human sliding clamp. Here, we used a structural genomics approach to address the prospect of broader-spectrum inhibition, in particular of β-clamps from Gram-negative bacterial targets.
View Article and Find Full Text PDFStructures of Trichomonas vaginalis macrophage migratory inhibitory factor.
Acta Crystallogr F Struct Biol Commun
December 2024
Article Synopsis
- Trichomonas vaginalis is a one-celled parasite that causes trichomoniasis, the most common nonviral STD worldwide, and it uses mimicry of human proteins to evade the immune system.
- The parasite produces a protein called TvMIF, which helps it survive stress, boosts prostate cell growth, and triggers inflammation, paralleling the effects of human MIF.
- Recent studies have revealed the structure of TvMIF, showing it has a similar shape to human versions, suggesting that understanding this protein can aid in developing new drugs.
: The chikungunya virus (CHIKV), transmitted by infected Aedes mosquitoes, has caused a significant number of infections worldwide. In Brazil, the emergence of the CHIKV-ECSA genotype in 2014 posed a major public health challenge due to its association with more severe symptoms. : This study aimed to shed new light on the host immune response by examining the whole-blood transcriptomic profile of both CHIKV-acute and chronically infected individuals from Feira de Santana, Bahia, Brazil, a region heavily affected by CHIKV, Dengue, and Zika virus epidemics.
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- Leishmaniasis is a rare but underreported disease in the U.S., primarily affecting travelers and migrants, with an annual incidence of only a few dozen cases, making true rates difficult to ascertain.
- From September 2021 to August 2022, a national reference laboratory tested 218 specimens, identifying 50.5% as positive, mostly linked to subgenus species causing cutaneous or mucocutaneous diseases.
- The study underscores the need for improved molecular testing and reveals a higher-than-reported incidence of mucosal leishmaniasis and greater genetic diversity within species found in the Americas.
Crystal structures of NAD(P)H nitroreductases from Klebsiella pneumoniae.
Acta Crystallogr F Struct Biol Commun
August 2024
Article Synopsis
- Klebsiella pneumoniae (Kp) is a major global health concern due to its ability to cause severe infections and resist multiple drugs, making research on its enzymes crucial for developing effective antibiotics like nitrofurantoin.
- This study presents crystal structures of two Kp nitroreductases (Kp-NRs) at high resolutions, detailing their unique structural features, including their αβ folds and variations in specific loops.
- The findings suggest that these enzymes may play a role in detoxifying harmful compounds and activating nitrofuran drugs, indicating their potential significance in combating Kp infections.
Efficacy of the bumped kinase inhibitor BKI-1708 against the cyst-forming apicomplexan parasites Toxoplasma gondii and Neospora caninum in vitro and in experimentally infected mice.
Maria Cristina Ferreira de Sousa Dennis Imhof Kai Pascal Alexander Hänggeli Ryan Choi Matthew A Hulverson
Int J Parasitol Drugs Drug Resist
August 2024
Article Synopsis
- Toxoplasma gondii and Neospora caninum are significant pathogens causing health issues globally, and Bumped Kinase Inhibitors (BKIs) represent a promising class of drugs targeted at combating these infections.
- BKI-1708, a specific BKI, has shown strong in vitro potency against these pathogens while maintaining high safety for human cells, indicated by its minimal effect on human foreskin fibroblast viability.
- In animal studies, BKI-1708 demonstrated an ability to reduce parasite loads in pregnant mice without affecting their pregnancy outcomes, highlighting its potential as a treatment for these infections.
Article Synopsis
- Researchers have identified calcium-dependent protein kinase 1 (CDPK1) in the protozoan responsible for cryptosporidiosis as a promising target for new therapies.
- A specific compound, a pyridopyrimidinone, was found to effectively inhibit CdPK1 and prevent the growth of various strains of the parasite in host cells.
- Although the compound showed low systemic exposure after oral dosing, it achieved high concentrations in the gastrointestinal tract and demonstrated some effectiveness in animal models of the disease.
Article Synopsis
- Metastatic castration-resistant prostate cancer is still incurable, despite recent treatments, and tumors show increased glycolysis as they progress.
- The study introduces BKIDC-1553, a new small-molecule compound that inhibits glycolysis specifically in prostate cancer cells without causing severe toxicity, and demonstrates promising results in preclinical models.
- BKIDC-1553 shows effective growth inhibition in various prostate cancer models and has safety and pharmacokinetic properties that suggest it’s ready for clinical trials to treat advanced prostate cancer.
Article Synopsis
- The text discusses an apicomplexan parasite that causes persistent diarrhea, focusing on developing calcium-dependent protein kinase 1 inhibitors, known as bumped kinase inhibitors (BKIs), which show promise in combating this parasite.
- BKI-1748, a specific inhibitor, shares similarities with quinine but has better efficacy against the parasite without the severe side effects associated with quinine, and it significantly affects the structure of the parasite.
- Research using mass spectrometry identified several proteins that BKI-1748 binds to, particularly those involved in RNA binding and modification, suggesting it interacts with crucial cellular processes like translation and RNA processing.
Article Synopsis
- Oral drug absorption, particularly of clofazimine, can be significantly affected by diarrhea associated with infections like cryptosporidiosis in HIV-infected adults.
- A population pharmacokinetic model using data from a study of 23 participants revealed that severe diarrhea can reduce clofazimine bioavailability by more than sixfold.
- Understanding these effects is crucial for optimizing dosing regimens to improve treatment outcomes for patients experiencing gastrointestinal issues.
Objectives: This study evaluated the performance of recombinant receptor binding domain (RBD) protein-based enzyme-linked immunosorbent assays (RBD-ELISAs) for detecting anti-SARS-CoV-2 immunoglobulin (Ig) G and IgM antibodies.
Methods: In this study, 705 sera from SARS-CoV-2-infected individuals and 315 sera from healthy individuals were analyzed.
Results: The RBD-ELISA IgG exhibited high specificity (99.
Article Synopsis
- Previous studies indicated that the compounds artemisone, artemiside, and BKI-1748 are effective against T. gondii through different mechanisms, suggesting potential synergistic effects when used together.
- Experimental results showed that the combination of these compounds significantly lowered the inhibition constants (IC) compared to individual treatments, with noticeable changes in cellular structure of the parasite when treated collectively.
- However, when tested in live mice, the combined treatment did not reduce T. gondii infection levels in the brain, and the promising in vitro findings did not translate effectively to the in vivo model, highlighting challenges in applying lab results to real-life scenarios.
Article Synopsis
- Congenital toxoplasmosis is a significant issue in both humans and animals, causing abortion and fetal abnormalities.
- The CDPK1 inhibitor BKI-1748 demonstrated safety in humans and effectiveness against Toxoplasma gondii in lab studies and mouse models.
- In sheep infected during pregnancy, BKI-1748 treatment began 48 hours post-infection successfully prevented abortion and congenital infection, with treated sheep showing minimal symptoms compared to untreated ones.
Article Synopsis
- Pathogenic free-living amoebae (pFLA) pose serious risks for central nervous system infections, making it crucial to find new chemical agents to fight these pathogens.
- The study focuses on glucokinase (Glck), a metabolic enzyme with minimal similarity to human counterparts, as a promising target for developing inhibitors.
- Using a novel "shotgun" multifragment kinetic target-guided synthesis (KTGS) strategy, researchers identified 12 effective inhibitors against three different pFLA glucokinase enzymes, showcasing KTGS's effectiveness even in the absence of detailed structural information.
Article Synopsis
- Infectious intestinal protozoan pathogens significantly contribute to health issues globally, particularly affecting children in low- and middle-income countries due to their underdeveloped immune systems and undernutrition.
- * The severity of symptoms in infected children can range from no symptoms to life-threatening conditions, influenced by various factors like nutritional status, immune response, and gut microbiome composition.
- * Damage to intestinal cells by these parasites can hinder nutrient absorption, leading to long-term consequences such as stunted growth and reduced cognitive development; existing treatments may also adversely affect gut health.
Characterization of a family I inorganic pyrophosphatase from Legionella pneumophila Philadelphia 1.
Acta Crystallogr F Struct Biol Commun
October 2023
Article Synopsis
- * Inorganic pyrophosphatases (PPases) break down PP into orthophosphates, preventing toxic buildup and providing usable phosphate for biosynthesis.
- * The study reports a crystal structure of L. pneumophila's family I PPase at high resolution, revealing its hexameric structure and preference for Mg as a cofactor, which is significant due to the bacterium's link to Legionnaires' disease.
Article Synopsis
- Around 50,000 children under 5 die annually from diarrhea caused by a protozoan parasite, with no effective drugs or vaccines currently available.
- Researchers conducted a high throughput screening (HTS) of compounds to find potential drugs targeting a protein called N-myristoyltransferase (NMT), which is a validated target in similar parasites.
- Two promising compounds were identified and tested against NMT, revealing different binding site conformations that offer insight for designing new selective inhibitors.
Article Synopsis
- Cryptosporidium is a gut pathogen that particularly affects people with weakened immune systems, such as those with HIV, and the CRYPTOFAZ trial in Malawi tested clofazimine's effectiveness for treating this infection.
- The study used various diagnostic methods, including qPCR and ELISA, to examine 586 individuals and monitor those who were part of the trial for pathogen shedding and other co-infections.
- The findings revealed that while qPCR was more sensitive for detecting Cryptosporidium, ELISA had more variable results; additionally, a new Cryptosporidium species was found, and enterotoxigenic E. coli was also linked to diarrhea in some participants.
Article Synopsis
- * Researchers utilized phylogenetic and epidemiological models to map YFV transmission patterns over different epidemic seasons and identified areas of high infection risk linked to low vaccination rates in major urban centers.
- * By analyzing the genomic data, the study revealed three distinct YFV lineages and demonstrated the connectivity between the endemic North and the extra-Amazonian region, suggesting that genomics combined with eco-epidemiology can enhance understanding and strategies for controlling the virus.
SARS-CoV-2, the etiologic agent of the COVID-19 pandemic, has had an enduring impact on global public health. However, SARS-CoV-2 is only one of multiple pathogenic human coronaviruses (CoVs) to have emerged since the turn of the century. CoVs encode for several nonstructural proteins (nsps) that are essential for viral replication and pathogenesis.
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- The Chikungunya virus poses a significant public health threat in the Americas, with over 120,000 cases and 51 fatalities reported in 2023.
- Paraguay was the most affected, accounting for 46 of those deaths.
- Researchers used advanced genomic, phylodynamic, and epidemiologic methods to study and understand the current chikungunya epidemic in Paraguay.