Antimalarial Drug Discovery: Structural Insights

Sergey Lunev

Antimalarial Drug Discovery: Structural Insights

Vertaalde titel van de bijdrage: Geneesmiddelontwikkeling tegen malaria: structureel inzicht

Sergey Lunev

Drug Design

Onderzoeksoutput: Thesis fully internal (DIV)

1631 Downloads (Pure)

Samenvatting

Ondanks rapporten over de eliminatie van malaria uit verschillende regio’s, blijft de ziekte een vernietigende invloed hebben op de wereld. Jaarlijks worden er nog steeds miljoenen mensen geïnfecteerd en sterven er honderdduizenden mensen aan de ziekte. Daarnaast belemmert het de ontwikkeling van de aangedane, endemische gebieden. De opkomende fenotypische- en klinische resistentie tegen de beschikbare medicatie zorgt ervoor dat een toevoer van nieuwe medicijnen hard nodig is. De wedloop tegen resistentie vraagt om grote inzet op versnelling van de ontdekking en validatie van nieuwe geneesmiddeltargets, parallel aan de ontwikkeling van nieuwe geneesmiddelen, afgifte-strategieën en het voorkomen van resistentie. Dit proefschrift is primair gericht op het leveren van structurele informatie voor de identificatie van geneesmiddeltargets en het ontwikkelen van validatiemethodiek.
Wij bieden een vernieuwende methode aan voor specifieke modulatie van eiwitactiviteit: de Protein Interference Assay (PIA). Deze techniek maakt gebruik van structurele informatie over een eiwitsysteem om functionele mutanten te genereren. De mutanten zijn in staat om zich samen te voegen met hun wild-type tegenhangers, waardoor de eiwitactiviteit verandert. Dit creëert de mogelijkheid om uiterst specifiek te interfereren met de eiwitactiviteit in vitro. Bovendien is er de mogelijkheid tot in(ex) vivo interferentie, door deze mutanten tot overexpressie te brengen in Plasmodium parasieten, gevolgd door fenotype-analyse en targetvalidatie.
Omdat de target-eiwitten worden onderzocht middels hun mutagene kopieën, worden er een aantal algemene uitdagingen omzeild zoals de peperdure ontwikkeling van een enzymremmer, onbetrouwbare genetische manipulatietechnieken, of dubbelzinnige in vivo resultaten vanwege slecht transport, chemische afbraak van geneesmiddelen of localisatieproblemen.
Voorts wordt er structureel onderzoek gerapporteerd over verscheidene veelbelovende geneesmiddeltargets voor Plasmodium falciparum.

Vertaalde titel van de bijdrage	Geneesmiddelontwikkeling tegen malaria: structureel inzicht
Originele taal-2	English
Kwalificatie	Doctor of Philosophy
Begeleider(s)/adviseur	Dömling, Alex, Supervisor Wrenger, Carsten, Supervisor, Externe Persoon Groves, Matthew, Co-supervisor Hirsch, Anna, Beoordelingscommissie Quax, W. J., Beoordelingscommissie Slotboom, Dirk, Beoordelingscommissie Wunderlich, G., Beoordelingscommissie, Externe Persoon
Datum van toekenning	29-mei-2018
Plaats van publicatie	[Groningen]
Uitgever	University of Groningen
Gedrukte ISBN's	978-94-034-0778-4
Elektronische ISBN's	978-94-034-0777-7
Status	Published - 2018

Toegang tot document

Title and contentsFinal publisher's version, 287 KB
Chapter 1Final publisher's version, 206 KB
Chapter 2Final publisher's version, 1,63 MB
Chapter 3Final publisher's version, 3,22 MB
Chapter 4Final publisher's version, 3,8 MB
Chapter 5Final publisher's version, 6,99 MB
Chapter 6Final publisher's version, 4,22 MB
Chapter 7Final publisher's version, 2,24 MB
Chapter 8Final publisher's version, 2,21 MB
AppendixFinal publisher's version, 0,98 MB
Complete thesisFinal publisher's version, 14,7 MB
PropositionsFinal publisher's version, 74 KB

Handle.net

Permanente koppeling

Citeer dit

@phdthesis{c16f9b200cfa41d98776cba4bb9a9e01,

title = "Antimalarial Drug Discovery: Structural Insights",

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.",

author = "Sergey Lunev",

year = "2018",

language = "English",

isbn = "978-94-034-0778-4",

publisher = "University of Groningen",

}

TY - THES

T1 - Antimalarial Drug Discovery: Structural Insights

AU - Lunev, Sergey

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

M3 - Thesis fully internal (DIV)

SN - 978-94-034-0778-4

PB - University of Groningen

CY - [Groningen]

ER -