23 research outputs found
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 âundruggableâ 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>âAlkyl Arylglycines by Organocatalytic Asymmetric Transfer Hydrogenation of <i>N</i>âAlkyl 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 BrĂžnsted 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 lateâstage 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)âH activation of tryptophan (Trp) is well documented, the resurgence of radical chemistry is opening new avenues for the CâH functionalization of other aromatic sideâchains. 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
Nicotinic Acetylcholine Receptor Labeled with a Tritiated, Photoactivatable Agonist:Â A New Tool for Investigating the Functional, Activated State â
Stapled Vasoactive Intestinal Peptide (VIP) Derivatives Improve VPAC<sub>2</sub> Agonism and Glucose-Dependent Insulin Secretion
Agonists
of vasoactive intestinal peptide receptor 2 (VPAC<sub>2</sub>) 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 VPAC<sub>2</sub>. 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 VPAC<sub>2</sub> agonism, peptide secondary structure, protease stability, and cell
membrane permeability. VIP analogues showing significantly enhanced
VPAC<sub>2</sub> 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