Stress Response and Artemisinin Resistance in Malaria Parasite
Abstract
In malaria, drug resistance is a major treat to disease control efforts. Unfortunately, there is a significant knowledge gap in our understanding of the molecular mechanisms behind these phenomena. The current report provides an update in our efforts to explored the role of GRP78, a protein chaperone from the stress response, in arteminisin resistant parasites. The GRP78 expression at the mRNA and protein levels was evaluated in artemisinin sensitive and resistant Plasmodium falciparum strains. The results indicated a low base line GRP78 protein levels in the drug resistant parasites, and these levels did not increase significantly upon artemisinin exposure in any of the strains evaluated. A role for the chaperone in the recovery period after drug exposure will be investigated during the last period of this award. Additionally, P. falciparum GRP78 was expressed and purified from a heterologous system. There combinant protein was used to characterize the binding of GRP78 inhibitors identified in the literature and determine its crystallographic structure. The inhibitors were also evaluated in the growth inhibition activity against P. falciparum. Two inhibitors that preferentially affected PfGRP78 were evaluated on their effect of the chaperone levels in vitro. Only one inhibitor was identified as targeting the chaperone, and it was used to explore the role of GRP78 on malaria parasite survival upon artemsisin exposure.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2018
- Accession Number
- AD1057198
Entities
People
- Juan C. Pizarro
Organizations
- Tulane University of Louisiana