Identification of potent and orally efficacious phosphodiesterase inhibitors in Cryptosporidium parvum-infected immunocompromised male mice

Jubilee Ajiboye, José E. Teixeira, Makafui Gasonoo, Ethan B. Mattice, Bethany Korwin-Mihavics, Peter Miller, Alexandra C. Cameron, Erin Stebbins, Scott D. Campbell, David W. Griggs, Thomas Spangenberg, Marvin J. Meyers () and Christopher D. Huston ()
Additional contact information
Jubilee Ajiboye: Burlington
José E. Teixeira: Burlington
Makafui Gasonoo: 3501 Laclede Avenue
Ethan B. Mattice: Burlington
Bethany Korwin-Mihavics: Burlington
Peter Miller: Burlington
Alexandra C. Cameron: Burlington
Erin Stebbins: Burlington
Scott D. Campbell: 1100 South Grand Boulevard
David W. Griggs: 1100 South Grand Boulevard
Thomas Spangenberg: Route de Crassier 1
Marvin J. Meyers: 3501 Laclede Avenue
Christopher D. Huston: Burlington

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Cryptosporidium parvum and C. hominis are parasites that cause life-threatening diarrhea in children and immunocompromised people. There is only one approved treatment that is modestly effective for children and ineffective for AIDS patients. Here, screening 278 compounds from the Merck KGaA, Darmstadt, Germany collection and accelerated follow-up enabled by prior investigation of the compounds identifies a series of pyrazolopyrimidine human phosphodiesterase (PDE)-V (hPDE-V) inhibitors with potent anticryptosporidial activity and efficacy following oral administration in C. parvum-infected male mice. The lead compounds affect parasite host cell egress, inhibit both C. parvum and C. hominis, work rapidly, and have minimal off-target effects in a safety screening panel. Interestingly, the hPDE-V inhibitors sildenafil and the 4-aminoquinoline compound 7a do not affect Cryptosporidium. C. parvum expresses one PDE (CpPDE1) continuously during asexual growth, the inhibited life stage. According to homology modeling and docking, the lead compounds interact with CpPDE1. Bulkier amino acids (Val900 and His884) in the CpPDE1 active site replace alanines in hPDE-V and block sildenafil binding. Supporting this, sildenafil kills a CRISPR-engineered Cryptosporidium CpPDE1 V900A mutant. The CpPDE1 mutation also alters parasite susceptibility to pyrazolopyrimidines. CpPDE1 is therefore a validated pyrazolopyrimidine molecular target to exploit for target-based optimization for improved anticryptosporidial development.

Date: 2024
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DOI: 10.1038/s41467-024-52658-y

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