Irreversible inhibition of DNA polymerase ß by small-molecule mimics of a DNA lesion.

Abasic sites are ubiquitous DNA lesions that are mutagenic and cytotoxic but are removed by the base excision repair pathway. DNA polymerase ß carries out two of the four steps during base excision repair, including a lyase reaction that removes the abasic site from DNA following incision of its 5'-phosphate. DNA polymerase ß is overexpressed in cancer cells and is a potential anticancer target. Recently, DNA oxidized abasic sites that are produced by potent antitumor agents were shown to inactivate DNA polymerase ß. A library of small molecules whose structures were inspired by the oxidized abasic sites was synthesized and screened for the ability to irreversibly inhibit DNA polymerase ß. One candidate (3a) was examined more thoroughly, and modification of its phosphate backbone led to a molecule that irreversibly inactivates DNA polymerase ß in solution (IC50 ≈ 21 µM), and inhibits the enzyme's lyase activity in cell lysates. A bisacetate analogue is converted in cell lysates to 3a. The bisacetate is more effective in cell lysates, more cytotoxic in prostate cancer cells than 3a and potentiates the cytotoxicity of methyl methanesulfonate between 2- and 5-fold. This is the first example of an irreversible inhibitor of the lyase activity of DNA polymerase ß that works synergistically with a DNA damaging agent.

Bridging the gap in peripheral nerve repair with 3D printed and bioprinted conduits.

Over the past two decades, a number of fabrication methods, including 3D printing and bioprinting, have emerged as promising technologies to bioengineer nerve conduits that closely replicate features of the native peripheral nerve, with the aim of augmenting or supplanting autologous nerve grafts. 3D printing and bioprinting offer the added advantage of rapidly creating composite peripheral nerve matrices from micron-scaled units, using an assortment of synthetic, natural and biologic materials. In this review, we explore the evolution of automated 3D manufacturing technologies for the development of peripheral nerve conduits and discuss aspects of conduit design, based on microarchitecture, material selection, cell and protein inclusion, and mechanical properties, as they are adaptable to 3D printing. Additionally, we highlight advancements in the application of bio-imaging modalities toward the fabrication of patient-specific nerve conduits. Lastly, we outline regulatory as well as clinical challenges that must be surmounted for the translation of 3D printing and bioprinting technology to the clinic. As a whole, this review addresses topics that may situate 3D manufacturing at the forefront of fabrication technologies that are exploited for the generation of future revolutionary therapies like in situ printing of peripheral nerves.