One health therapeutics: Target-Based drug development for cryptosporidiosis and other apicomplexa diseases

Voorhis, Wesley C. Van; Hulverson, Matthew A.; Choi, Ryan; Huang, Wenlin; Arnold, Samuel; Schaefer, Deborah A.; Betzer, Dana P.; Vidadala, Rama Subba Rao; Lee, Sangun; Whitman, Grant R.; Barrett, Lynn K.; Maly, Dustin J.; Riggs, Michael W.; Fan, Erkang; Kennedy, Thomas J.; Tzipori, Saul; Doggett, J. Stone; Winzer, Pablo; Anghel, Nicoleta; Imhof, Dennis; Müller, Joachim; Hemphill, Andrew; Ferre, Ignacio; Sánchez-Sánchez, Roberto; Ortega‐Mora, Luis Miguel; Ojo, Kayode K.

doi:10.1016/j.vetpar.2020.109336

Cited by 20 publications

(19 citation statements)

References 58 publications

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“…Therefore, CDPKs are thought to be potential therapeutic targets against the parasites (Su et al 2022 ). After understanding the crystal structures of CDPKs having a gatekeeper glycine residue, specific bumped-kinase inhibitors (BKIs) were developed that inhibit CDPK1 functions through the hydrophobic pocket that opens up next to the glycine residue (Huang et al 2017 ; Hulverson, et al 2017a , b ; Van Voorhis et al 2021 ). Calcium-dependent protein kinase 6 (CpCDPK6) (cgd4_3330) is a hypothetical protein of the CDPK family that regulates sporozoite invasion, gliding, and parasite egress (Billker et al 2009 ; Wernimont et al 2010 ; Zhang et al 2021 ).…”

Section: Novel Drug Targetsmentioning

confidence: 99%

An update on Cryptosporidium biology and therapeutic avenues

et al. 2022

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Cryptosporidium species has been identified as an important pediatric diarrheal pathogen in resource-limited countries, particularly in very young children (0–24 months). However, the only available drug (nitazoxanide) has limited efficacy and can only be prescribed in a medical setting to children older than one year. Many drug development projects have started to investigate new therapeutic avenues. Cryptosporidium ’s unique biology is challenging for the traditional drug discovery pipeline and requires novel drug screening approaches. Notably, in recent years, new methods of oocyst generation, in vitro processing, and continuous three-dimensional cultivation capacities have been developed. This has enabled more physiologically pertinent research assays for inhibitor discovery. In a short time, many great strides have been made in the development of anti- Cryptosporidium drugs. These are expected to eventually turn into clinical candidates for cryptosporidiosis treatment in the future. This review describes the latest development in Cryptosporidium biology, genomics, transcriptomics of the parasite, assay development, and new drug discovery.

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Section: Novel Drug Targetsmentioning

confidence: 99%

An update on Cryptosporidium biology and therapeutic avenues

et al. 2022

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“…Among them, one, K292-0423, displayed the ability to inhibit the enzyme activity of Cp CDPK2A as well as significant in vitro anti-cryptosporidial activity at the micromole level. In recent years, several bumped kinase inhibitors of Cp CDPK1 have become the leading candidates for the development of novel treatment of cryptosporidiosis ( Van Voorhis et al, 2021 ). Previously, using a similar approach, we also identified a Cp CDPK1 inhibitor (F083-0116) with inhibitory activities on the enzyme and C. parvum growth ( Su et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Calcium-Dependent Protein Kinase 2A, a Potential Drug Target Against Cryptosporidiosis

Shu

Chu

et al. 2022

Front. Microbiol.

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Calcium-dependent protein kinases (CDPKs) are important in calcium influx, triggering several biological processes in Cryptosporidium spp. As they are not present in mammals, CDPKs are considered promising drug targets. Recent studies have characterized CpCDPK1, CpCDPK3, CpCDPK4, CpCDPK5, CpCDPK6, and CpCDPK9, but the role of CpCPK2A remains unclear. In this work, we expressed recombinant CpCDPK2A encoded by the cgd2_1060 gene in Escherichia coli and characterized the biologic functions of CpCDPK2A using qRT-PCR, immunofluorescence microscopy, immuno-electron microscopy, and in vitro neutralization. The results revealed that CpCDPK2A protein was highly expressed in the apical region of sporozoites and merozoites and in macrogamonts. Monoclonal or polyclonal antibodies against CpCDPK2A failed to block the invasion of host cells. Among the 44 candidate inhibitors from molecular docking of CpCDPK2A, one inhibitor was identified as having a potential effect on both Cryptosporidium parvum growth and CpCDPK2A enzyme activities. These data suggest that CpCDPK2A may play some roles during the development of C. parvum and might be a potential drug target against cryptosporidiosis.

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“…Analysis of protein kinase binding pockets for design of potent and selective kinase inhibitors suggests 5 domains within the ATP binding sites that can be occupied by a compound [70] , [89] . Of these 5 domains, the more widely reported examples of selective inhibitors are those that target a hydrophobic pocket adjoining an atypically small “gatekeeper residue” [90] , [67] , [26] , [75] , [111] . Several Apicomplexan CDPKs that are essential for maintenance of fundamental cellular processes and parasite survival have smaller gatekeeper residues creating an enlarged hydrophobic pocket.…”

Section: Targeting Cdpks Of Malaria Parasite For Drug Development and Functional Characterizationmentioning

confidence: 99%

CDPKs: The critical decoders of calcium signal at various stages of malaria parasite development

Sharma

Choudhury

Roy

et al. 2021

Computational and Structural Biotechnology Journal

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One health therapeutics: Target-Based drug development for cryptosporidiosis and other apicomplexa diseases

Cited by 20 publications

References 58 publications

An update on Cryptosporidium biology and therapeutic avenues

An update on Cryptosporidium biology and therapeutic avenues

Characterization of Calcium-Dependent Protein Kinase 2A, a Potential Drug Target Against Cryptosporidiosis

CDPKs: The critical decoders of calcium signal at various stages of malaria parasite development

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