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PhD Student: Drugs against malaria
Category:
Phd

Description:

In the absence of an effective malaria vaccine, malaria control depends, to a large extent, on chemotherapeutic interventions for both prevention and cure. It is therefore crucial that all efforts are made to prolong the longevity and efficacy of existing antimalarials and prevent the emergence of resistance to novel drugs, particularly in light of early stage resistance to artemisinin combination therapy in form of delayed parasite clearance in vivo. In addition, efforts should be intensified to develop new drugs with novel modes of action. The project will focus on understanding the mode of action and the mechanism of resistance of quinoline antimalarial drugs, which together with artemisinin derivatives form the backbone of malaria chemotherapy. The second part of the project will deal with the clinical drug candidate SC83288 and how the compound kills the parasite. The project will involve the generation of P. falciparum mutants using CRISPR/Cas9 genome editing technology to validate candidate genes. The project will further include biochemical drug binding and transport assays and proteomics and metabolomics to identify molecular targets. The project will be conducted in collaboration with the Sumaya Biotec company. The hosting laboratory is a leader in malaria drug discovery and profiling. Up to three PhD positions are vacant.

The salary will be according to TVL E13 65 % including social benefits, which will amount to a gross pay of approximately 30,000 € per year.

References:

1. Pegoraro S, Duffey M, Otto TD, Wang Y, Rösemann R, Baumgartner R, Fehler SK, Lucantoni L, Avery VM, Moreno-Sabater A, Mazier D, Vial HJ, Strobl S, Sanchez CP, Lanzer M. (2017) SC83288 is a clinical development candidate for the treatment of severe malaria. Nat Commun 8:14193.

2. Bakouh N, Bellanca S, Nyboer B, Moliner Cubel S, Karim Z, Sanchez CP, Stein WD, Planelles G and Lanzer M (2017) Iron is a substrate of the Plasmodium falciparum chloroquine resistance transporter PfCRT in Xenopus oocytes. J Biol Chem 292: 16109-16121.

3. Summers RL, Dave A, Dolstra TJ, Bellanca S, Marchetti RV, Nash MN, Richards SN, Goh V, Schenk RL, Stein WD, Kirk K, Sanchez CP, Lanzer M* and Martin RE* (2014) Diverse mutational pathways converge on saturable chloroquine transport via the malaria parasite's chloroquine resistance transporter. Proc Natl Acad Sci U S A 111: E1759-E1767.

4. Sanchez CP, Liu CH, Mayer S, Nurhasanah A, Cyrklaff M, Mu J, Ferdig MT, Stein WD and Lanzer M (2014) A HECT ubiquitin-protein ligase as a novel candidate gene for altered quinine and quinidine responses in Plasmodium falciparum. PLoS Genet 10: e1004382.

5. Bellanca S, Summers RL, Meyrath M, Dave A, Nash MN, Dittmer M, Sanchez CP, Stein WD, Martin RE and Lanzer M (2014) Multiple drugs compete for transport via the Plasmodium falciparum chloroquine resistance transporter at distinct but interdependent sites. J Biol Chem 289: 36336-36351.

 

Methods that will be used: CRISPR/Cas9 genome editing technology, drug transport and binding studies, metabolomics, proteomics, P. falciparum cell culture, microscopy and imaging technologies

Cooperation partners: The project will be conducted in collaboration with the Sumaya Biotec company.

Personal qualifications: Qualified candidate should have a degree from an internationally accredited institution of higher education. Applications from all fields of natural sciences and medicine are welcome. Interest in interdisciplinary collaborations is highly desirable. Candidates with a migration background are welcome to apply.

Keywords: Malaria, Plasmodium; drug; CRISPR/Cas9; genome editing; metabolomics; proteomics; imaging technology.

 

Application deadline: 30. Sep 2018

Start of PhD project: 1. Nov 2018

Contact details: Prof. Michael Lanzer Project No: Lanzer0218

If you are interested in this position, please apply through the Heidelberg Biosciences International Grduate School HBIGS http://www.hbigs.uni-heidelberg.de