Antimalarial Drug Discovery: Structural Insights

Sergey Lunev

Research output: ThesisThesis fully internal (DIV)

1182 Downloads (Pure)

Abstract

Despite reported elimination from many regions, malaria remains a devastating burden, annually infecting millions and killing hundreds of thousands people and delaying economic development in endemic regions. Rising phenotypic and clinical resistance against all antimalarials urgently requires a continuous supply of new drugs with sufficient clinical lifespan to allow for further drug development. This task requires significant efforts in speeding discovery and validating new antimalarial drug targets, in parallel to the development of novel drugs, delivery strategies and resistance prevention. This thesis is primarily focused on providing means and structural information for new drug target identification and validation.
We propose a novel method for specific modulation of target protein activity – the Protein Interference Assay (PIA). Structural information of the target system is used to generate functionally affected mutant species. These mutants are able to recombine with their wild type counterparts, modulating their activity and thus providing an opportunity for highly specific interference with the target proteins in vitro. Furthermore, overexpression of such mutants within Plasmodium parasites would allow in(ex) vivo interference and subsequent phenotypic analysis and drug target validation.
The target proteins are probed using their own mutagenic copies, thus bypassing common challenges such as expensive inhibitor design, (often) unreliable genetic manipulation techniques or ambiguous in vivo results of the drug tests due to the poor transport, drug degradation or localization.
Furthermore, structural investigation of several promising drug targets within P. falciparum is reported.
Translated title of the contributionGeneesmiddelontwikkeling tegen malaria: structureel inzicht
Original languageEnglish
QualificationDoctor of Philosophy
Supervisors/Advisors
  • Dömling, Alex, Supervisor
  • Wrenger, Carsten, Supervisor, External person
  • Groves, Matthew, Co-supervisor
  • Hirsch, Anna, Assessment committee
  • Quax, W. J., Assessment committee
  • Slotboom, Dirk, Assessment committee
  • Wunderlich, G., Assessment committee, External person
Award date29-May-2018
Place of Publication[Groningen]
Publisher
Print ISBNs978-94-034-0778-4
Electronic ISBNs978-94-034-0777-7
Publication statusPublished - 2018

Cite this