Cyclic tetrapeptide HDAC inhibitors as potential therapeutics for spinal muscular atrophy: Screening with iPSC-derived neuronal cells.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder that is caused by inactivating mutations in the Survival of motor neuron 1 (SMN1) gene, resulting in decreased SMN protein expression. Humans possess a paralog gene, SMN2, which contains a splicing defect in exon 7 leading to diminished expression of full-length, fully functional SMN protein. Increasing SMN2 expression has been a focus of therapeutic development for SMA.

Discovery of a highly selective caspase-3 substrate for imaging live cells.

Caspases are a family of cysteine proteases that are well-known for their roles in apoptosis and inflammation. Recent studies provide evidence that caspases are also integral to many additional cellular processes, such as differentiation and proliferation. Likewise, aberrant caspase activity has been implicated in the progression of several diseases, including neurodegenerative disorders, cancer, cardiovascular disease, and sepsis.

Selective inhibition of initiator versus executioner caspases using small peptides containing unnatural amino acids.

Caspases are fundamental to many essential biological processes, including apoptosis, differentiation, and inflammation. Unregulated caspase activity is also implicated in the development and progression of several diseases, such as cancer, neurodegenerative disorders, and sepsis. Unfortunately, it is difficult to determine exactly which caspase(s) of the 11 isoforms that humans express is responsible for specific biological functions.

Selective detection and inhibition of active caspase-3 in cells with optimized peptides.

Caspases are a family of cysteine-aspartyl proteases that are well recognized for their essential roles in apoptosis and inflammation. Recently, caspases have also been linked to the promotion of other biologically important phenomena, such as cellular differentiation and proliferation. Dysregulation of the multifaceted and indispensable activities of caspases has been globally linked to several diseases, including cancer and neurodegenerative disorders; however, the specific caspase members responsible for these diseases have yet to be assigned.

Small-molecule procaspase activators identified using fluorescence polarization.

Wake up, protein! Small molecules that directly activate proteins are rare and their discovery opens new avenues for the development of drugs and chemical tools to probe the functions and mechanisms of protein targets. To address the one-sided dichotomy between enzyme inhibition and activation, we describe a series of procaspase activators as chemical tools in the study of caspase biology.

Selective detection of caspase-3 versus caspase-7 using activity-based probes with key unnatural amino acids.

Caspases are required for essential biological functions, most notably apoptosis and pyroptosis, but also cytokine production, cell proliferation, and differentiation. One of the most well studied members of this cysteine protease family includes executioner caspase-3, which plays a central role in cell apoptosis and differentiation. Unfortunately, there exists a dearth of chemical tools to selectively monitor caspase-3 activity under complex cellular and in vivo conditions due to its close homology with executioner caspase-7.

Discovery of HDAC Inhibitors That Lack an Active Site Zn(2+)-Binding Functional Group.

Natural and synthetic histone deacetylase (HDAC) inhibitors generally derive their strong binding affinity and high potency from a key functional group that binds to the Zn(2+) ion within the enzyme active site. However, this feature is also thought to carry the potential liability of undesirable off-target interactions with other metalloenzymes. As a step toward mitigating this issue, here, we describe the design, synthesis, and structure-activity characterizations of cyclic α3β-tetrapeptide HDAC inhibitors that lack the presumed indispensable Zn(2+)-binding group.

Potential Agents for Treating Cystic Fibrosis: Cyclic Tetrapeptides that Restore Trafficking and Activity of ΔF508-CFTR.

Cystic fibrosis (CF) is a loss-of-function disease caused by mutations in the CF transmembrane conductance regulator (CFTR) protein, a chloride ion channel that localizes to the apical plasma membrane of epithelial cells. The most common form of the disease results from the deletion of phenylalanine-508 (ΔF508), leading to the accumulation of CFTR in the endoplasmic reticulum with a concomitant loss of chloride flux. We discovered that cyclic tetrapeptides, such as 11, 14, and 15, are able to correct the trafficking defect and restore cell surface activity of ΔF508-CFTR.

Pd(II)-catalyzed o-C-H acetoxylation of phenylalanine and ephedrine derivatives with MeCOOO(t)Bu/Ac2O.

Pd(II)-catalyzed ortho C-H acetoxylation of triflate protected phenethyl- and phenpropylamines has been achieved with tert-butyl peroxyacetate as the stoichiometric oxidant and either DMF or CH(3)CN as the promoter. The reaction was found to tolerate a large variety of functional groups and could be combined with subsequent intramolecular amination to afford functionalized indoline derivatives.