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

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

  • Biochem Biophys Res Commun. 2019 Sep 10;517(1):125-131. doi: 10.1016/j.bbrc.2019.07.031.
Christopher Schwake 1,  Michael R Baldwin 2,  William Bachovchin 3,  Shreeya Hegde 4,  James Schiemer 2,  Carolyn Okure 4,  Andrew E Levin 5,  Edouard Vannier 6,  Toshihiko Hanada 7,  Athar H Chishti 8
Affiliations

Affiliations

  • 1 Graduate Program in Cellular, Molecular, and Developmental Biology, USA; Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, 02111, USA.
  • 2 Graduate Program in Cellular and, Molecular Physiology, USA; Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, 02111, USA.
  • 3 Graduate Program in Pharmacology and Experimental Therapeutics, USA; Department of Developmental, Molecular and Chemical Biology, USA; Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, 02111, USA.
  • 4 Graduate Program in Pharmacology and Experimental Therapeutics, USA; Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, 02111, USA.
  • 5 Kephera Diagnostics, Framingham, MA, 01702, USA.
  • 6 Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, MA, 02111, USA.
  • 7 Department of Developmental, Molecular and Chemical Biology, USA.
  • 8 Graduate Program in Cellular, Molecular, and Developmental Biology, USA; Graduate Program in Cellular and, Molecular Physiology, USA; Graduate Program in Pharmacology and Experimental Therapeutics, USA; Department of Developmental, Molecular and Chemical Biology, USA; Graduate Program in Molecular Microbiology, USA; Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA, 02111, USA. Electronic address: [email protected].
PMID: 31311649 DOI: 10.1016/j.bbrc.2019.07.031
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.

Keywords

Atazanavir; Babesia microti; Erythrocyte; HIV protease inhibitor; Lopinavir; Signal peptide peptidase (SPP).

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