Title:Drug Target Validation Methods in Malaria - Protein Interference Assay (PIA) as a Tool for Highly Specific Drug Target Validation
Volume: 18
Issue: 9
Author(s): Kamila A. Meissner, Sergey Lunev, Yuan-Ze Wang, Marleen Linzke, Fernando de Assis Batista, Carsten Wrenger and Matthew R. Groves*
Affiliation:
- Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9700 AD, Groningen,Netherlands
Keywords:
Drug target validation, in vivo specificity, malaria, oligomerisation, protein Interference, protein: protein interactions.
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.
