Disinfection using effective antimicrobials is essential in preventing the spread of infectious diseases. This COVID‐19 pandemic has brought the need for effective disinfectants to greater attention due to the fast transmission of SARS‐CoV‐2. Current active ingredients in disinfectants are small molecules that microorganisms can develop resistance against after repeated long‐term use and may penetrate the skin, causing harmful side‐effects. To this end, a series of membrane‐disrupting polyionenes that contain quaternary ammoniums and varying hydrophobic components is synthesized. They are effective against bacteria and fungi. They are also fast acting against clinically isolated drug resistant strains of bacteria. Formulating them with thickeners and nonionic surfactants do not affect their killing efficiency. These polyionenes are also effective in preventing infections caused by nonenveloped and enveloped viruses. Their effectiveness against mouse coronavirus (i.e., mouse hepatitis virus‐MHV) depends on their hydrophobicity. The polyionenes with optimal compositions inactivates MHV completely in 30 s. More importantly, the polyionenes are effective in inhibiting SARS‐CoV‐2 by >99.999% within 30 s. While they are effective against the microorganisms, they do not cause damage to the skin and have a high oral lethal dose. Overall, these polyionenes are promising active ingredients for disinfection and prevention of viral and microbial infections.
Vaccinia‐related kinase 1 (VRK1), a serine/threonine mitotic kinase, is widely over‐expressed in dividing cells and regarded as a cancer drug target primarily due to its function as an early response gene in cell proliferation. However, the mechanism of VRK1 phosphorylation and substrate activation is not well understood. More importantly even the molecular basis of VRK1 interaction with its cofactor, adenosine triphosphate (ATP), is unavailable to‐date. As designing specific inhibitors remains to be the major challenge in kinase research, such a molecular understanding will enable us to design ATP‐competitive specific inhibitors of VRK1. Here we report the molecular characterization of VRK1 in complex with AMP‐PNP, a non‐hydrolyzable ATP‐analog, using NMR titration followed by the co‐crystal structure determined upto 2.07 Å resolution. We also carried out the structural comparison of the AMP‐PNP bound‐form with its apo and inhibitor‐bound counterparts, which has enabled us to present our rationale toward designing VRK1‐specific inhibitors.
The human vaccinia-related kinase 1 (VRK1), is a mitotic kinase, involved in cell division regulation and carcinogenesis. VRK1 phosphorylates the histone H3 at Thr3 and Ser10, which is a critical event for initiating chromosome condensation during mitosis. The deregulation of VRK1 can affect chromatin architecture and Ph.D. Thesis, School of Biological Sciences, NTU XI | P a g e structure of VRK1 in complex with AMP-PNP was determined at a resolution of 2.07Å, revealing several key residues such as Asp132, Phe134, Met131, Ser181 and Val196 of VRK1 important for ATP interaction, supported by NMR studies. A structural comparison with the inhibitor-bound VRK1, its paralogs and other mitotic kinases enabled us to identify hotspots to design more specific ATPcompetitive VRK1 inhibitor. In the second part of thesis, the molecular interaction of VRK1 with histone H3 was characterized. To this end, attempts were made to obtain nucleosome core particle (NCP) in complex with VRK1. While our preliminary studies using mobility shift electrophoretic assay indicated complex formation, nonetheless, obtaining the homogenous NCP-VRK1 complex remained a challenge. To achieve this purpose, further optimization is required to unravel the VRK1 and histone H3 interaction mechanism, which together with the ATP binding studies, can offer more strategies for the development of novel VRK1 inhibitors with better specificity and potency in the future.
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