Dr. Ashwani Sharma
5232 Villigen PSI
Ashwani completed his doctoral studies at ICGEB (New Delhi India), on a project that aimed at the structural and functional characterization of malaria parasite proteins involved in crosstalk with the human cell components. He performed his postdoctoral research at PSI and then at EPFL where he successfully applied a combination of structural and biophysical techniques to study mammalian tubulin-protein and tubulin-drug complexes. Subsequently, with the support from a Novartis FreeNovation grant and a SNF Spark grant, he initiated a project together with Dr. Natacha Gaillard on the Apicomplexan microtubule cytoskeleton at PSI. Additionally, Ashwani is leading and managing Biophysics Resources at PSI (https://www.psi.ch/en/lbr/facilities).
Eukaryotic parasites belonging to the phylum Apicomplexa invade host cells via a complex and active process which involves the coordinated action of multiple organelles located at the apical end of the parasites (apical complex, APC). The APC comprises of a tubulin based conoid, multiple secretory organelles (rhoptries and micronemes) and inter-conoidal microtubules (MTs). Although, the APC is implicated in parasite invasion by secreting parasite proteins into the host cells, to date, molecular details of the role of the MTs in APC secretion and host cell invasion remains largely unknown. Towards this end, we are using recombinant protein technologies in combination with biochemical and structural methods to discover the interactions of host and parasite MTs with the parasite proteins involved in host cell invasion.
Inhibition of cell division by using tubulin targeting, antimitotic compounds has been the most successful strategy for cancer treatment up to now. Implementing a similar strategy to arrest parasite replication using apicomplexan tubulin specific inhibitors offers a completely new and attractive avenue towards anti-apicomplexan drug discovery. Our research interest is to exploit the structural peculiarities of apicomplexan tubulin drug-binding sites in comparison to their mammalian counterparts to develop novel anti-tubulin drugs specific for protozoan parasites.
AIMS Award, Principal Investigator
Award from Atomwise Inc. for AI based anti-parasite drug discovery
Spark, SNF, Principal Investigator
Host cytoskeleton manipulation by Apicomplexan parasites: structural and functional investigation of the RON complex
Novartis Freenovation Grant, Co-Principal Investigator
Towards the Structure Based Design of Broad Spectrum Anti-Apicomplexan Drugs
EMBO Long Term Fellowship
Mühlethaler T, Olieric N, Ehrhard VA, Wranik M, Standfuss J, Sharma A, et al.
Crystallization systems for the high-resolution structural analysis of tubulin-ligand complexes
In: Inaba H, ed. Microtubules. Methods and protocols. Methods in molecular biology. New York: Humana Press; 2022:349-374. https://doi.org/10.1007/978-1-0716-1983-4_23
Kashyap AS, Fernandez-Rodriguez L, Zhao Y, Monaco G, Trefny MP, Yoshida N, et al.
GEF-H1 signaling upon microtubule destabilization is required for dendritic cell activation and specific anti-tumor responses
Cell Reports. 2019; 28(13): 3367-3380.e1. https://doi.org/10.1016/j.celrep.2019.08.057
Sharma A, Sáez-Calvo G, Olieric N, de Asís Balaguer F, Barasoain I, Lamberth C, et al.
Quinolin-6-yloxyacetamides are microtubule destabilizing agents that bind to the colchicine site of tubulin
International Journal of Molecular Sciences. 2017; 18(7): 1336 (11 pp.). https://doi.org/10.3390/ijms18071336
Purification, crystallization and preliminary crystallographic studies of C-terminal RNA recognition motif (RRM-3) of human ELAV-type RNA-binding protein 3 (ETR-3).
Acta Crystallogr Sect F Struct Biol Cryst Commun. 69(Pt 10), 1107-09 (2013).DOI: http://dx.doi.org/10.1107/S1744309113023439.
Utility of anion and cation combinations for phasing of protein structures.
J Struct Funct Genomics. 13(3), 135-43 (2012).DOI: http://dx.doi.org/10.1007/s10969-012-9137-3.
Fatty acid induced remodeling within the human liver fatty acid-binding protein.
J Biol Chem. 286(36), 31924-8 (2011).DOI: http://dx.doi.org/10.1074/jbc.M111.270165.
Structural insights into thioredoxin-2:a component of malaria parasite protein secretion machinery.
Scientific Reports 1:179, (2011).DOI: http://dx.doi.org/10.1038/srep00179.
Crystal structure of soluble domain of malaria sporozoite protein UIS3 in complex with lipid.
J Biol Chem. 283(35), 24077-88 (2008).DOI: http://dx.doi.org/10.1074/jbc.M801946200.
Role of Plasmodium falciparum thrombospondin-related anonymous protein in host-cell interactions.
Malar J. 7:63, (2008).DOI: http://dx.doi.org/10.1186/1475-2875-7-63.