Design of a Small Molecule That Stimulates VEGFA Informed from an Expanded Encyclopedia of RNA Fold-Small Molecule Interactions

Vascular Endothelial Growth Factor A(VEGFA) stimulates angiogenesis in human endothelial cells and increasing its expression is a potential treatment for heart failure, currently accomplished via gene or mRNA therapy. Herein, we describe a designed small molecule (TGP-377) that specifically and potently enhances VEGFA expression by targeting of a non-coding microRNA that regulates its expression. This investigation was initiated by studying the RNA motifs that bound small molecules from a subset of the AstraZeneca compound collection. A two-dimensional combinatorial screen (2DCS) revealed preferences in small molecule chemotypes that bind RNA and preferences in the RNA motifs that bind small molecules, increasing the known information by 20-fold. Analysis of this dataset against the RNA-mediated pathways that regulate VEGFA defined that the microRNA-377 precursor (pre-miR-377), which represses VEGFAmRNA translation, is druggable in a selective manner. The compound potently and specifically upregulated VEGFA in Human Umbilical Vein Endothelial Cells (HUVEC). Analysis of the proteome and angiogenic phenotype affected by TGP-377 demonstrated that the compound is highly potent and selective. These studies illustrate the power of 2DCS to define molecular recognition events between “undruggable” biomolecules and small molecules and the ability of sequence-based design to deliver efficacious compounds that target RNA and precisely and potently modulate disease-associated pathways.</p

Direct Synthesis of <i>N</i>‑Alkyl Arylglycines by Organocatalytic Asymmetric Transfer Hydrogenation of <i>N</i>‑Alkyl Aryl Imino Esters

The organocatalytic asymmetric transfer hydrogenation of <i>N</i>-alkyl aryl imino esters for the direct synthesis of <i>N</i>-alkylated arylglycinate esters is reported. High yields and enantiomeric ratios were obtained, and tolerance to a diverse set of functional groups facilitated the preparation of more complex molecules as well as intermediates for active pharmaceuticals. A simple recycling protocol was developed for the Brønsted acid catalyst which could be reused through five cycles with no loss of activity or selectivity

Late-Stage Functionalization of Histidine in Unprotected Peptides

The late‐stage functionalization (LSF) of peptides represents a valuable strategy for the design of potent peptide pharmaceuticals by enabling rapid exploration of chemical diversity and offering novel opportunities for peptide conjugation. While the C(sp2)−H activation of tryptophan (Trp) is well documented, the resurgence of radical chemistry is opening new avenues for the C−H functionalization of other aromatic side‐chains. Herein, we report the first example of LSF at C2 of histidine (His) utilizing a broad scope of aliphatic sulfinate salts as radical precursors. In this work, the exquisite selectivity for histidine functionalization was demonstrated through the alkylation of complex unprotected peptides in aqueous media. Finally, this methodology was extended for the installation of a ketone handle, providing an unprecedented anchor for selective oxime/hydrazone conjugation at histidine

2,6-Quinolinyl derivatives as potent VLA-4 antagonists

International audienc

Stapled Vasoactive Intestinal Peptide (VIP) Derivatives Improve VPAC₂ Agonism and Glucose-Dependent Insulin Secretion

Agonists of vasoactive intestinal peptide receptor 2 (VPAC₂) stimulate glucose-dependent insulin secretion, making them attractive candidates for the treatment of hyperglycaemia and type-II diabetes. Vasoactive intestinal peptide (VIP) is an endogenous peptide hormone that potently agonizes VPAC₂. However, VIP has a short serum half-life and poor pharmacokinetics in vivo and is susceptible to proteolytic degradation, making its development as a therapeutic agent challenging. Here, we investigated two peptide cyclization strategies, lactamisation and olefin-metathesis stapling, and their effects on VPAC₂ agonism, peptide secondary structure, protease stability, and cell membrane permeability. VIP analogues showing significantly enhanced VPAC₂ agonist potency, glucose-dependent insulin secretion activity, and increased helical content were discovered; however, neither cyclization strategy appeared to effect proteolytic stability or cell permeability of the resulting peptides