Repurposing the Kinase Inhibitor Mavelertinib for Giardiasis Therapy

Michaels, Samantha A.; Hulverson, Matthew A.; Whitman, Grant R.; Tran, Linh T; Choi, Ryan; Fan, Erkang; McNamara, Case W.; Love, Melissa S.; Ojo, Kayode K.

doi:10.1128/aac.00017-22

Cited by 4 publications

(5 citation statements)

References 53 publications

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“…Disulfiram, a thiuram disulfide drug used to treat alcohol abuse disorder, also exhibited in vitro anti-giardia activity with a minimum lethal concentration of 1.23 μM and modest activity in vivo with a 21% cure rate in mice against Giardia [53]. In addition, mavelertinib, an EFGR-TKI (tyrosine-kinase inhibitor), has also displayed effective activity in mice infected with G. intestinalis [54]. Several anticancer drugs have also been suggested to be repurposed against protozoa including G. intestinalis.…”

Section: Recent Drug Discovery Efforts Against Giardiasismentioning

confidence: 99%

Perspectives on the drug discovery of intestinal protozoan parasites

Thakur,

Sharma,

Negi

et al. 2024

Intestinal Parasites - New Developments in Diagnosis, Treatment, Prevention and Future Directions [Working Title]

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The intestinal protozoan parasites pose serious health concerns, infecting more than one billion individuals every year and mainly causing diarrhea in infants and adults. Main pathogens include Giardia intestinalis, Entamoeba histolytica, Cyclospora cayetanensis, and Cryptosporidium spp. causing giardiasis, amoebiasis, cyclosporiasis, and cryptosporidiosis, respectively. The drug arsenal to treat these diseases is limited (<25 drugs are in clinical use) for the treatment of all protozoal infections. The existing treatment options are decades of years old (discovered in 1930–1980s) and have limitations such as low therapeutic index, toxic side effects during long-term treatment, and drug resistance. Therefore, urgent renewed drug discovery efforts are needed to tackle these neglected protozoal diseases. This chapter discusses the current status of treatment options and their limitations, along with current drug discovery efforts. We conclude that the knowledge gained in the genomic and post-genomic era should be appropriately harnessed to accelerate the futuristic drug discovery process in this field.

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Section: Recent Drug Discovery Efforts Against Giardiasismentioning

confidence: 99%

Perspectives on the drug discovery of intestinal protozoan parasites

Thakur,

Sharma,

Negi

et al. 2024

Intestinal Parasites - New Developments in Diagnosis, Treatment, Prevention and Future Directions [Working Title]

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“…Only one species in this genus, G. duodenalis, causes clinical giardiasis in humans and most mammals, although there is a complex of various assemblages that differ in host specificity. The assemblages are subcategories of G. duodenalis characterized by subtle genomic differences but wide mammalian host diversity [ 35 ]. The assemblages are named from A to H, and some are further subdivided by genotype.…”

Section: The Causative Parasitesmentioning

confidence: 99%

The Gut-Wrenching Effects of Cryptosporidiosis and Giardiasis in Children

Prabakaran,

Weible,

Champlain

et al. 2023

Microorganisms

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Cryptosporidium species and Giardia duodenalis are infectious intestinal protozoan pathogens that cause alarming rates of morbidity and mortality worldwide. Children are more likely to have clinical symptoms due to their less developed immune systems and factors such as undernutrition, especially in low- and middle-income countries. The severity of the symptoms and clinical manifestations in children may vary from asymptomatic to life-threatening depending on the Cryptosporidium species/G. duodenalis strains and the resulting complex stepwise interactions between the parasite, the host nutritional and immunologic status, and the gut microbiome profile. Structural damages inflicted by both parasites to epithelial cells in the large and small intestines could severely impair children’s gut health, including the ability to absorb nutrients, resulting in stunted growth, diminished neurocognitive development, and other long-term effects. Clinically approved cryptosporidiosis and giardiasis drugs have broad antimicrobial effects that have incomprehensible impacts on growing children’s gut health.

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“…For in vitro Giardia assays, we used a click beetle green (CBG99) luciferase-based reporter system that was developed for quantitative bioluminescence readouts of growth in trophozoites ( 13 – 15 ). The CBG99 reporter gene is under the control of the glutamate dehydrogenase promoter, which is highly expressed in the G. lamblia trophozoite stage, making it useful for monitoring growth even in mouse infection models ( 15 ).…”

Section: Observationmentioning

confidence: 99%