Current strategies for the design of PROTAC linkers: a critical review

PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules consisting of two ligands; an “anchor” to bind to an E3 ubiquitin ligase and a “warhead” to bind to a protein of interest, connected by a chemical linker. Targeted protein degradation by PROTACs has emerged as a new modality for the knock down of a range of proteins, with the first agents now reaching clinical evaluation. It has become increasingly clear that the length and composition of the linker play critical roles on the physicochemical properties and bioactivity of PROTACs. While linker design has historically received limited attention, the PROTAC field is evolving rapidly and currently undergoing an important shift from synthetically tractable alkyl and polyethylene glycol to more sophisticated functional linkers. This promises to unlock a wealth of novel PROTAC agents with enhanced bioactivity for therapeutic intervention. Here, the authors provide a timely overview of the diverse linker classes in the published literature, along with their underlying design principles and overall influence on the properties and bioactivity of the associated PROTACs. Finally, the authors provide a critical analysis of current strategies for PROTAC assembly. The authors highlight important limitations associated with the traditional “trial and error” approach around linker design and selection, and suggest potential future avenues to further inform rational linker design and accelerate the identification of optimised PROTACs. In particular, the authors believe that advances in computational and structural methods will play an essential role to gain a better understanding of the structure and dynamics of PROTAC ternary complexes, and will be essential to address the current gaps in knowledge associated with PROTAC design

Development of seed polyphenols in berries from Vitis vinifera L. cv. Shiraz

Polyphenols extracted from the seeds of Vitis vinifera L. cv. Shiraz berries were monitored during berry development. Initially seeds were green, plump and had pliable seed coats, but beginning at veraison the seeds browned in colour, became desiccated and the seed coats hardened. Isolated polyphenols consisted of flavan-3-of monomers ((+)-catechin, (-)-epicatechin and (-)-epicatechin-3-O-gallate) and procyanidins. The procyanidins were maximal in the 3 weeks prior to veraison, increasing little during this period. The amounts of flavan-3-ol monomers increased 5-fold during this same period of time, indicating that the procyanidins and the flavan-3-ol monomers accumulate at different stages. Beginning at veraison, amounts of all polyphenols declined and changed in composition. The decrease in amount followed second-order kinetics. Polyphenol changes after veraison could be explained by oxidation and therefore, electron paramagnetic resonance (EPR) spectroscopy was used to follow the potential development of radical species in the developing seeds. Spectra consistent with a phenoxyl radical were observed in the developing seeds. The concentration of radicals remained low until veraison but then increased, reaching a maximum three weeks later, declining slowly thereafter. Changes in radical intensity together with other documented changes in the seed are consistent with an oxidative event occurring during fruit ripening

Ciclones em Superfície nas Latitudes Austrais: Parte I - Revisão Bibliográfica

Resumo Com o objetivo de organizar o conhecimento sinótico sobre ciclones em superfície em latitudes austrais, este trabalho (o primeiro de um conjunto de dois) apresenta uma síntese das principais características de quatro tipos de ciclones: extratropical do tipo Bjerknes e Solberg, extratropical do tipo Shapiro e Keyser, tropical e subtropical. Ao longo do texto são apresentados modelos conceituais bem como os mecanismos de ciclogênese, intensificação e ciclólise de cada tipo de ciclone. As principais diferenças entre os quatros tipos de ciclones em superfície estão nas estruturas horizontais e verticais dos campos de temperatura e vorticidade relativa