HIV protease inhibitors block parasite signal peptide peptidases and prevent growth of Babesia microti parasites in erythrocytes.

Abstract

Malaria and babesiosis are bloodborne protozoan infections for which the emergence of drug-resistant strains poses a threat. Our previous phage display cDNA screens established the essentiality of Plasmodium falciparum signal peptide peptidase (SPP) in asexual development at the blood stage of malaria infection. Given the structural similarities between SPP inhibitors and HIV protease inhibitors, we screened ten HIV protease inhibitors and selected Lopinavir and Atazanavir for their ability to inhibit PfSPP activity. Using a transcription-based assay, we observed that Lopinavir inhibits both parasite-and host-derived SPP activities whereas Atazanavir inhibited only parasite derived SPP activity. Consistent with their inhibitory effect on Plasmodium growth, both Lopinavir and Atazanavir strongly inhibited intraerythrocytic Babesia microti growth ex vivo. Moreover, Lopinavir prevented the steep rise in Babesia microti parasitemia typically observed in rag1-deficient mice. Our data provide first evidence that inhibition of parasite-derived SPPs by HIV protease inhibitors offers a promising therapeutic avenue for the treatment of severe babesiosis and infections caused by other Apicomplexa parasites.

• Authors: Christopher Schwake, Michael R Baldwin, William Bachovchin, Shreeya Hegde, James Schiemer, Carolyn Okure, Andrew E Levin, Edouard Vannier, Toshihiko Hanada, Athar H Chishti
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 517 Issue 1 Pg. 125-131 (09 10 2019) ISSN: 1090-2104 [Electronic] United States
• PMID: 31311649 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• HIV Protease Inhibitors
• Protozoan Proteins
• Lopinavir
• Atazanavir Sulfate
• Aspartic Acid Endopeptidases
• signal peptide peptidase

Topics

• Animals
• Aspartic Acid Endopeptidases (antagonists & inhibitors, metabolism)
• Atazanavir Sulfate (pharmacology, therapeutic use)
• Babesia microti (drug effects, growth & development, metabolism)
• Babesiosis (drug therapy, parasitology)
• Erythrocytes (parasitology)
• HIV Protease Inhibitors (pharmacology, therapeutic use)
• Humans
• Lopinavir (pharmacology, therapeutic use)
• Mice
• Parasitemia (drug therapy, parasitology)
• Protozoan Proteins (antagonists & inhibitors, metabolism)