A Curious Case for Development of Kinase Inhibitors as Antigiardiasis Treatments Using Advanced Drug Techniques

Abstract

Giardiasis is a neglected parasitic diarrheal disease that is particularly associated with poverty. Current treatment options are limited in the face of growing resistance, but the reduced kinome of Giardia lamblia increases the likelihood of identifying nonredundant essential kinases as potential drug targets. Repurposing known and newly identified kinase inhibitors in drug development programs for novel giardiasis therapeutics could therefore be a cost-effective and time saving approach. Innovative improvements to physiologically-based pharmacokinetic modeling coupled with emerging imaging technologies and a CRISPRinterference method could accelerate progress toward the goal of more effective giardiasis therapeutics based on kinase inhibition.

Repurposing the Kinase Inhibitor Mavelertinib for Giardiasis Therapy

“…Gut dysbiosis can complicate giardiasis treatment in malnourished children, a major population group for Giardia therapeutics. Given its high prevalence in resource-limited regions, giardiasis is a neglected infectious disease that could benefit from additional treatment options based on drug repurposing platforms ( 8 , 11 , 30 ) that will address these concerns.…”

“…Until recently, minimal effort has been dedicated to developing new anti-infectives against G. lamblia , despite the great clinical need. Renewed interest in giardiasis therapeutic discovery has spiked due to advances in G. lamblia reporter systems that are ideal for whole-cell high-throughput screens and in vivo screening of pharmaceutical libraries ( 8 – 11 ). The ReFRAME library could accelerate the process of finding new treatments against giardiasis and other infectious parasitic diseases afflicting millions in countries that have limited drug discovery and development resources ( 14 – 17 ).…”

“…With 37 compounds from pharmaceutical companies approved for various human clinical uses and >250 currently in clinical trials ( 31 ), finding kinase inhibitors that could be readily repurposed for treating giardiasis and other indications among this pool is highly desirable. Giardia protein kinases are not specifically targeted by any available giardiasis drugs, making inhibitors of these enzymes attractive agents for development of therapeutics against sensitive and resistant strains ( 8 , 30 , 32 ). It should be noted that the data obtained in this study do not fully support a conclusion that the primary molecular target of mavelertinib in Giardia is a protein kinase, and more target identification work is needed.…”

“…Other potential therapeutics, like quinacrine, are effective in treating metronidazole-resistant giardiasis but have been withdrawn from the U.S. market due to poor tolerability ( 5 – 7 ). Even with increasing emphasis on new approaches to expand treatment options, development of new drugs against Giardia lamblia is limited ( 8 ). Given the public health need, accelerated development of alternative drugs for clinical use against all Giardia strains, including those with resistance to first-line treatments, is warranted.…”

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

“…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.…”