Microtubules are hollow, cylindrical
polymers of the protein α,
β tubulin, that interact mechanochemically with a variety of
macromolecules. Due to their mechanically robust nature, microtubules
have gained attention as tracks for precisely directed transport of
nanomaterials within lab-on-a-chip devices. Primarily due to the unusually
negative tail-like C-termini of tubulin, recent work demonstrates
that these biopolymers are also involved in a broad spectrum of intracellular
electrical signaling. Microtubules and their electrostatic properties
are discussed in this Review, followed by an evaluation of how these
biopolymers respond mechanically to electrical stimuli, through microtubule
migration, electrorotation and C-termini conformation changes. Literature
focusing on how microtubules act as nanowires capable of intracellular
ionic transport, charge storage, and ionic signal amplification is
reviewed, illustrating how these biopolymers attenuate ionic movement
in response to electrical stimuli. The Review ends with a discussion
on the important questions, challenges, and future opportunities for
intracellular microtubule-based electrical signaling.
The heterodimer of DNA excision repair protein ERCC‐1 and DNA repair endonuclease XPF (ERCC1‐XPF) is a 5′–3′ structure‐specific endonuclease essential for the nucleotide excision repair (NER) pathway, and it is also involved in other DNA repair pathways. In cancer cells, ERCC1‐XPF plays a central role in repairing DNA damage induced by chemotherapeutics including platinum‐based and cross‐linking agents; thus, its inhibition is a promising strategy to enhance the effect of these therapies. In this study, we rationally modified the structure of F06, a small molecule inhibitor of the ERCC1‐XPF interaction (Molecular Pharmacology, 84, 2013 and 12), to improve its binding to the target. We followed a multi‐step computational approach to investigate potential modification sites of F06, rationally design and rank a library of analogues, and identify candidates for chemical synthesis and in vitro testing. Our top compound, B5, showed an improved half‐maximum inhibitory concentration (IC50) value of 0.49 µM for the inhibition of ERCC1‐XPF endonuclease activit, and lays the foundation for further testing and optimization. Also, the computational approach reported here can be used to develop DNA repair inhibitors targeting the ERCC1‐XPF complex.
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