Drug Target Validation Methods in Malaria - Protein Interference Assay (PIA) as a Tool for Highly Specific Drug Target Validation

Author(s)

Meissner, Kamila A. ; Lunev, Sergey ; Wang, Yuan-Ze ; Linzke, Marleen ; Batista, Fernando de Assis ; Wrenger, Carsten ; Groves, Matthew R.

• Document type: Review article
• Source: CURRENT DRUG TARGETS; v. 18, n. 9, p. 1069-1085, 2017.
• Web of Science Citations: 4

Abstract

Background: The validation of drug targets in malaria and other human diseases remains a highly difficult and laborious process. In the vast majority of cases, highly specific small molecule tools to inhibit a proteins function in vivo are simply not available. Additionally, the use of genetic tools in the analysis of malarial pathways is challenging. These issues result in difficulties in specifically modulating a hypothetical drug target's function in vivo. Objective: The current ``toolbox{''} of various methods and techniques to identify a protein's function in vivo remains very limited and there is a pressing need for expansion. New approaches are urgently required to support target validation in the drug discovery process. Method: Oligomerisation is the natural assembly of multiple copies of a single protein into one object and this self-assembly is present in more than half of all protein structures. Thus, oligomerisation plays a central role in the generation of functional biomolecules. A key feature of oligomerisation is that the oligomeric interfaces between the individual parts of the final assembly are highly specific. However, these interfaces have not yet been systematically explored or exploited to dissect biochemical pathways in vivo. Results and Conclusion: This mini review will describe the current state of the antimalarial toolset as well as the potentially druggable malarial pathways. A specific focus is drawn to the initial efforts to exploit oligomerisation surfaces in drug target validation. As alternative to the conventional methods, Protein Interference Assay (PIA) can be used for specific distortion of the target protein function and pathway assessment in vivo. (AU)

• FAPESP's process: 13/10288-1 - Analysis of the organelle biogenesis in Plasmodium falciparum by live cell imaging
• Grantee: Carsten Wrenger
• Support Opportunities: Regular Research Grants
• FAPESP's process: 12/12807-3 - Analysis of the redox status and its effect on the proliferation of Plasmodium falciparum in genetically different erythrocytes
• Grantee: Kamila Anna Meissner
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 14/23330-9 - Morphologic Analysis of the Apicoplast Formation in Plasmodium falciparum
• Grantee: Marleen Linzke
• Support Opportunities: Scholarships in Brazil - Doctorate