A General Approach to Optically Pure, α‑Methyl Non-Natural Amino Acids: Enabling Unique Peptides as Drug Candidates

An α-methyl, non-natural amino acid (NNAA) building block equipped with an alkyl halide tail that could be readily transformed into an organozinc was prepared. This single organometallic was cross-coupled to an array of heterocyclic electrophiles using the Pd-PEPPSI-IHeptCl catalyst to produce a wide selection of optically pure α-methyl NNAAs. With these in hand, non-natural peptides are being produced for evaluation in a variety of therapeutic areas in drug discovery

NRL- and CRX-guided gene network modulates photoreceptor presynapse size and positioning during retinal development

AbstractUnique morphologies of rod and cone photoreceptor presynaptic terminals permit the formation of synapses onto interneurons during retina development. We integrated multiple “omics” datasets of developing rod and S-cone-like photoreceptors and identified 719 genes that are regulated by NRL and CRX, critical transcriptional regulators of rod differentiation, as candidates for controlling presynapse morphology. In vivo knockdown of 72 candidate genes in the developing retina uncovered 26 genes that alter size and/or positioning of rod spherules in the outer plexiform layer. Co-expression of seven cDNAs with their cognate shRNAs rescued the rod presynapse phenotype. Loss of function of four genes in germline or by an AAV-mediated CRISPR/Cas9 strategy validated RNAi screen findings. A protein interaction network analysis of the 26 positive effectors revealed additional candidates in the NRL/CRX-regulated presynapse morphology-associated gene network. Follow-up knockdowns of two novel candidates support the proposed network. Our studies demonstrate a requirement of multiple components in a modular network for rod presynapse morphogenesis and provide a functional genomic framework for deciphering genetic determinants of morphological specification during development.Author SummaryThe relationship between neuronal morphology and function has been recognized for over 100 years. However, we still have poor understanding of genes and proteins that control morphogenesis of a specific neuron. In the current study, we address this connection between gene expression and neural morphology by identifying and knocking down a subset of expressed genes in rod photoreceptors. We ascertained a number of candidate genes controlling photoreceptor pre-synaptic terminal morphology, which is necessary for its connection with second-order neurons in the retinal circuit. Furthermore, we have curated a more plausible network of genes, either identified in our study or predicted, that are enriched for processes underlying photoreceptor morphogenesis. We suggest that our work will provide a framework for dissecting genetic basis of neuronal architecture and assist in better design of cell replacement therapies for retinal degeneration.</jats:sec

Novel irreversible peptidic inhibitors of transglutaminase 2

A novel peptidic scaffold was used to design a library of inhibitors that exhibit exceptional efficiency against tissue transglutaminase, providing a framework for the development of potent research tools.</jats:p

Parrotfish Size: A Simple yet Useful Alternative Indicator of Fishing Effects on Caribbean Reefs?

There is great need to identify simple yet reliable indicators of fishing effects within the multi-species, multi-gear, data-poor fisheries of the Caribbean. Here, we investigate links between fishing pressure and three simple fish metrics, i.e. average fish weight (an estimate of average individual fish size), fish density and fish biomass, derived from (1) the parrotfish family, a ubiquitous herbivore family across the Caribbean, and (2) three fish groups of “commercial” carnivores including snappers and groupers, which are widely-used as indicators of fishing effects. We hypothesize that, because most Caribbean reefs are being heavily fished, fish metrics derived from the less vulnerable parrotfish group would exhibit stronger relationships with fishing pressure on today’s Caribbean reefs than those derived from the highly vulnerable commercial fish groups. We used data from 348 Atlantic and Gulf Rapid Reef Assessment (AGRRA) reef-surveys across the Caribbean to assess relationships between two independent indices of fishing pressure (one derived from human population density data, the other from open to fishing versus protected status) and the three fish metrics derived from the four aforementioned fish groups. We found that, although two fish metrics, average parrotfish weight and combined biomass of selected commercial species, were consistently negatively linked to the indices of fishing pressure across the Caribbean, the parrotfish metric consistently outranked the latter in the strength of the relationship, thus supporting our hypothesis. Overall, our study highlights that (assemblage-level) average parrotfish size might be a useful alternative indicator of fishing effects over the typical conditions of most Caribbean shallow reefs: moderate-to-heavy levels of fishing and low abundance of highly valued commercial species