Investigation of Plasmodium kinase

inhibitors & ubiquitin signaling pathways

Graduate Mentor: Anna Truong | at331@duke.edu

Principal Investigator: Prof. Emily R. Derbyshire, PhD

Department of Chemistry

Duke University

Muser

Summer 2021 & Fall 2021 positions

229 millionnew malaria infections

in 2019

409 000people died of malaria

in 2019

Malaria is a major global health burden

World Malaria Report 2020: 20 Years of Global Progress and Challenges. Maier, A. G. et al. Trends in Parasitology 2019, 35 (6), 481–482.

Malaria parasite P. falciparum

undergoes a complex lifecycle

There is a continual and pressing need to study

Plasmodium biology to inform malaria drug discovery.

Project 1 :

In s i l ico docking studies of Plasmodium kinase inh ib i tors

Musyoka, T., Kanzi, A., Lobb, K. et al. Sci. Rep. 2016. 6,23690.

Aim: validate potential targets of

Plasmodium kinase inhibitors and

propose mechanisms of binding

through computational models

Methods:

• PyMol + AutoDock

Vina plugin

• Schrödinger Glide

Future directions:

• Experimental

validation

• Binding studies

Posfai, D. et al. Antimicrob Agents Chemother. 2018, 62 (4) e01799-17

Project 1 : Background

Relevant literature:

• Adderley, Jack et al. Parasite and host erythrocyte kinomics of

Plasmodium infection. Trends Parasitol. 2021, Volume 0, Issue 0.

DOI: https://doi.org/10.1016/j.pt.2021.01.002*

• Derbyshire, E.R., et al. Chemical Interrogation of the Malaria Kinome.

ChemBioChem. 2014, 15: 1920-1930

• Eubanks, A.L., et al. In silico Screening and Evaluation of Plasmodium

falciparum Protein Kinase 5 Inhibitors. ChemMedChem. 2018, 13,

2479-2483.

• Trott, O., Olson, AJ. AutoDock Vina: improving the speed and

accuracy of docking with a new scoring function, efficient optimization

and multithreading, J Comput Chem. 2010, 31(2): 455–461.

• Repasky, M.P., Shelley, M. and Friesner, R.A. Flexible ligand docking

with Glide. Current Protocols in Bioinformatics. 2007, 18: 8.12.1-

8.12.36.

*P. falciparum kinase tree:

Project 2 :

B iochemical in terrogat ion of Plasmodium ubiqui t in s ignal ing

Aim: identify protein-protein

interactions in P. falciparum

ubiquitination pathways and small

molecules as chemical probes

Methods:

• Molecular cloning

• Protein expression

& purification

• Assay development

Future directions:

• Binding studies

• Proteomic

analyses

Raphemot, R. et al. Cell Chem Biol 2019, 26 (3), 411-419.e7. Ponts, N. et al. J Biol Chem. 2011 286(46):40320-30.

Ubiquitin roles in Plasmodium blood stage:

Project 2: Background

Relevant literature:

• Komander D., Rape M. The Ubiquitin Code. Annu. Rev.

Biochem. 2012; 81:1, 203-229.

• Hamilton, M.J. et al. The ubiquitin system: an essential

component to unlocking the secrets of malaria parasite biology.

Mol Biosyst. 2014; 10(4): 715–723.

• Philip, N.; Haystead, T. A. Characterization of a UBC13 kinase

in Plasmodium falciparum. PNAS. 2007; 104 (19), 7845–7850.

• Raphemot, R. et al. Plasmodium PK9 Inhibitors Promote

Growth of Liver-Stage Parasites. Cell Chem. Biol. 2019; 26,

411-419.

• Mata-Cantero, L. et al. New insights into host-parasite ubiquitin

proteome dynamics in P. falciparum infected red blood cells

using a TUBEs-MS approach. J. Proteom. 2016; 139: 45-59 Ponts, N. et al. PLoS ONE. 2008, 3 (6), e2386.

Ubiquitin enzymatic cascade: