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1p.-6 fig., The cytoskeleton is the main communication/transport route within cells and many viruses abuse on this cellular machine to fulfil their cycle. We initially identified the interaction of a SARS-CoV-2 protein with tubulin using a proteomic analysis. We next confirmed the interaction and identified the viral protein domain involved through in vitro co-immunoprecipitation assays and analytical ultracentrifugation experiments. Then, we focused on unveiling the molecular mechanism of the interaction to determine if the SARS-CoV-2 protein promote a stable microtubule assembly (as roads for motors) or induce microtubule dynamics (as main force generation for transport). We have combined biochemical, biophysical and structural studies to determine the ratio of protein-protein interaction and the resulting effect on tubulin assembly. We have found that this protein domain is able to promote microtubule depolymerization into rings and tubulin assembly into non-functional filaments likely because a preference for tubulin curved-conformation. Importantly, this effect is not dependent on nucleotide or nucleotide hydrolysis. Finally, tubulin is a well-known target in cancer diseases and there are four of the seven tubulin druggable sites exploited on chemotherapy. Hence, we have analyzed the ability of microtubule stabilizing (MSA) and destabilizing agents (MDA) on disrupting the interaction of SARS-CoV-2 protein with tubulin. We have found that MSAs keep microtubule structures even in the presence of the viral protein, while the effect of MDAs varies depending on their mechanism of action., This research work was funded by Ministerio de Ciencia e Innovación and CSIC. It was also funded by the European Commission – NextGenerationEU (Regulation EU2020/2094), through CSIC's Global Health Platform (PTI Salud Global).

53 p.-7 fig.-1 tab.-1 schem.-1 graph. abst., Noscapine is a natural product first isolated from the opium poppy (Papaver somniferum L.) with anticancer properties. In this work, we report the synthesis and cellular screening of a noscapine-based library. A library of novel noscapine derivatives was synthesized with modifications in the isoquinoline and phthalide scaffolds. The so generated library, consisting of fifty-seven derivatives of the natural product noscapine, was tested against MDA-MB-231 breast cancer cells in a cellular proliferation assay (with a Z' > 0.7). The screening resulted in the identification of two novel noscapine derivatives as inhibitors of MDA cell growth with IC50 values of 5 µM and 1.5 µM, respectively. Both hit molecules have a five-fold and seventeen-fold higher potency, compared with that of lead compound noscapine (IC50 26 µM). The identified active derivatives retain the tubulin-binding ability of noscapine. Further testing of both hit molecules, alongside the natural product against additional cancer cell lines (HepG2, HeLa and PC3 cells) confirmed our initial findings. Both molecules have improved anti-proliferative properties when compared to the initial natural product, noscapine., We are also grateful to the Iran National Science Foundation (INSF, grant number 98026465) for financial support of this project and Shahid Beheshti University Research Council for providing facilities of to conduct this study. This work was supported by CSIC PIE 201920E111 (MAO).