Virtual Screening and Experimental Validation Identify Novel Inhibitors of the Plasmodium falciparum Atg8-Atg3 Protein-Protein Interaction

Adelaide U P Hain, Alexia S. Miller, Jelena Levitskaya, Jürgen Bosch

Research output: Contribution to journalArticle

Abstract

New therapies are needed against malaria, a parasitic infection caused by Plasmodium falciparum, as drug resistance emerges against the current treatment, artemisinin. We previously characterized the Atg8-Atg3 protein-protein interaction (PPI), which is essential for autophagy and parasite survival. Herein we illustrate the use of virtual library screening to selectively block the PPI in the parasite without inhibiting the homologous interaction in humans by targeting the A-loop of PfAtg8. This A-loop is important for Atg3 binding in Plasmodium, but is absent from the human Atg8 homologues. In this proof-of-concept study, we demonstrate a shift in lipidation state of PfAtg8 and inhibition of P.falciparum growth in both blood- and liver-stage cultures upon drug treatment. Our results illustrate how insilico screening and structure-aided drug design against a PPI can be used to identify new hits for drug development. Additionally, as we targeted a region of Atg8 that is conserved within apicomplexans, we predict that our small molecule will have cross-reactivity against other disease-causing apicomplexans, such as Toxoplasma, Cryptosporidium, Theileria, Neospora, Eimeria, and Babesia.

Original languageEnglish (US)
JournalChemMedChem
DOIs
StateAccepted/In press - 2016

Fingerprint

Plasmodium falciparum
Screening
Proteins
Parasites
Theileria
Digital Libraries
Pharmaceutical Preparations
Neospora
Drug therapy
Babesia
Eimeria
Cryptosporidium
Parasitic Diseases
Plasmodium
Drug Design
Autophagy
Toxoplasma
Drug Resistance
Liver
Malaria

Keywords

  • Autophagy
  • Drug design
  • Malaria
  • Protein-protein interactions
  • Virtual screening

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry
  • Molecular Medicine

Cite this

Virtual Screening and Experimental Validation Identify Novel Inhibitors of the Plasmodium falciparum Atg8-Atg3 Protein-Protein Interaction. / Hain, Adelaide U P; Miller, Alexia S.; Levitskaya, Jelena; Bosch, Jürgen.

In: ChemMedChem, 2016.

Research output: Contribution to journalArticle

@article{a5ac1b3104b54640be19988937620702,
title = "Virtual Screening and Experimental Validation Identify Novel Inhibitors of the Plasmodium falciparum Atg8-Atg3 Protein-Protein Interaction",
abstract = "New therapies are needed against malaria, a parasitic infection caused by Plasmodium falciparum, as drug resistance emerges against the current treatment, artemisinin. We previously characterized the Atg8-Atg3 protein-protein interaction (PPI), which is essential for autophagy and parasite survival. Herein we illustrate the use of virtual library screening to selectively block the PPI in the parasite without inhibiting the homologous interaction in humans by targeting the A-loop of PfAtg8. This A-loop is important for Atg3 binding in Plasmodium, but is absent from the human Atg8 homologues. In this proof-of-concept study, we demonstrate a shift in lipidation state of PfAtg8 and inhibition of P.falciparum growth in both blood- and liver-stage cultures upon drug treatment. Our results illustrate how insilico screening and structure-aided drug design against a PPI can be used to identify new hits for drug development. Additionally, as we targeted a region of Atg8 that is conserved within apicomplexans, we predict that our small molecule will have cross-reactivity against other disease-causing apicomplexans, such as Toxoplasma, Cryptosporidium, Theileria, Neospora, Eimeria, and Babesia.",
keywords = "Autophagy, Drug design, Malaria, Protein-protein interactions, Virtual screening",
author = "Hain, {Adelaide U P} and Miller, {Alexia S.} and Jelena Levitskaya and J{\"u}rgen Bosch",
year = "2016",
doi = "10.1002/cmdc.201500515",
language = "English (US)",
journal = "ChemMedChem",
issn = "1860-7179",
publisher = "John Wiley and Sons Ltd",

}

TY - JOUR

T1 - Virtual Screening and Experimental Validation Identify Novel Inhibitors of the Plasmodium falciparum Atg8-Atg3 Protein-Protein Interaction

AU - Hain, Adelaide U P

AU - Miller, Alexia S.

AU - Levitskaya, Jelena

AU - Bosch, Jürgen

PY - 2016

Y1 - 2016

N2 - New therapies are needed against malaria, a parasitic infection caused by Plasmodium falciparum, as drug resistance emerges against the current treatment, artemisinin. We previously characterized the Atg8-Atg3 protein-protein interaction (PPI), which is essential for autophagy and parasite survival. Herein we illustrate the use of virtual library screening to selectively block the PPI in the parasite without inhibiting the homologous interaction in humans by targeting the A-loop of PfAtg8. This A-loop is important for Atg3 binding in Plasmodium, but is absent from the human Atg8 homologues. In this proof-of-concept study, we demonstrate a shift in lipidation state of PfAtg8 and inhibition of P.falciparum growth in both blood- and liver-stage cultures upon drug treatment. Our results illustrate how insilico screening and structure-aided drug design against a PPI can be used to identify new hits for drug development. Additionally, as we targeted a region of Atg8 that is conserved within apicomplexans, we predict that our small molecule will have cross-reactivity against other disease-causing apicomplexans, such as Toxoplasma, Cryptosporidium, Theileria, Neospora, Eimeria, and Babesia.

AB - New therapies are needed against malaria, a parasitic infection caused by Plasmodium falciparum, as drug resistance emerges against the current treatment, artemisinin. We previously characterized the Atg8-Atg3 protein-protein interaction (PPI), which is essential for autophagy and parasite survival. Herein we illustrate the use of virtual library screening to selectively block the PPI in the parasite without inhibiting the homologous interaction in humans by targeting the A-loop of PfAtg8. This A-loop is important for Atg3 binding in Plasmodium, but is absent from the human Atg8 homologues. In this proof-of-concept study, we demonstrate a shift in lipidation state of PfAtg8 and inhibition of P.falciparum growth in both blood- and liver-stage cultures upon drug treatment. Our results illustrate how insilico screening and structure-aided drug design against a PPI can be used to identify new hits for drug development. Additionally, as we targeted a region of Atg8 that is conserved within apicomplexans, we predict that our small molecule will have cross-reactivity against other disease-causing apicomplexans, such as Toxoplasma, Cryptosporidium, Theileria, Neospora, Eimeria, and Babesia.

KW - Autophagy

KW - Drug design

KW - Malaria

KW - Protein-protein interactions

KW - Virtual screening

UR - http://www.scopus.com/inward/record.url?scp=84953931426&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84953931426&partnerID=8YFLogxK

U2 - 10.1002/cmdc.201500515

DO - 10.1002/cmdc.201500515

M3 - Article

C2 - 26748931

AN - SCOPUS:84953931426

JO - ChemMedChem

JF - ChemMedChem

SN - 1860-7179

ER -