Webinar 4: June 10th, 12.00-13.00 (SAST/CEST)

First talk:- Unusual protein trafficking mechanisms in Giardia lamblia

Speaker: Prof. Dr. Carmen Faso (Multidisciplinary Center for Infectious Diseases (MCID) / Institute of Cell Biology / Institute for Infectious Diseases (IFIK), University of Bern)

Abstract: Giardia lamblia is one of those parasites that is unlikely to make the headlines, yet it accounts for over 300 million cases of diarrheal disease worldwide and is a scourge of young children in resource-limited settings with poor access to clean water. From a biological perspective, Giardia lamblia cells present some of the most fascinating examples of extreme cell biology, such as the absence of entire organelle systems and the evolution of unusual protein trafficking routes implicated in parasite virulence. In my presentation, I shall attempt to highlight some of our more salient discoveries concerning these mechanisms, with a focus on exocytosis and endocytosis.

Second talk:- Structure-based discovery of Mitomycin C as a potential multi-stage pan-inhibitor of Plasmodium falciparum class 1a aminoacyl tRNA synthetase

Speaker: Dr. Fisayo Olotu (Research Unit in Bioinformatics, Rhodes University)

Abstract: The critical roles of Plasmodium falciparum aminoacyl tRNA synthetases (PfaaRSs) in the synthesis and fidelity of the plasmodial proteome at every life-cycle stage make them important antimalarial targets. So far, some of these proteins have been singly targeted to yield inhibitor compounds that are limited by incidences of resistance which can be overcome via pan-inhibition strategies. Here, for the first time, we report the identification and in vitro antiplasmodial validation of Mitomycin (MMC) as a potential pan-inhibitor of six class 1a (arginyl(A)-, cysteinyl(C), isoleucyl(I)-, leucyl(L), methionyl(M), and valyl(V)-) PfaaRSs which hypothetically may underlie its previously reported activity on the ribosomal RNA to inhibit protein translation and biosynthesis. Our combined in silico structure-based discovery strategies helped identify functional and druggable sites preferentially targeted by MMC in each of the plasmodial proteins: Ins1-Ins2 domain in Pf-ARS; anticodon binding domain in Pf-CRS; CP1-editing domain in Pf-IRS and Pf-MRS; C-terminal domain in Pf-LRS; and CP-core region in Pf-VRS. Molecular dynamics studies further revealed that MMC allosterically induced changes in the global structures of each protein, complementary with prominent structural perturbations across the functional domains of the proteins. More so, catalytic nucleotide and amino acid substrates were systematically altered by the binding of MMC, which culminated in the loss of key interactions with key active site residues.  This, in turn, accounted for the ultimate reduction in nucleotide-binding affinities across all the proteins as deduced from the binding energy calculations. Furthermore, MMC demonstrated IC50 < 5μM against the PfDd2 and 3D7 strains making it an ideal starting point for malarial drug development. We believe these findings from our study will be important in the current search for highly effective multi-stage antimalarial drugs.

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