Differential membrane binding of α/β-peptide foldamers: implications for cellular delivery and mitochondrial targeting.

The intrinsic pathway of apoptosis is regulated by the Bcl-2 family of proteins. Inhibition of the anti-apoptotic members represents a strategy to induce apoptotic cell death in cancer cells. We have measured the membrane binding properties of a series of peptides, including modified α/β-peptides, designed to exhibit enhanced membrane permeability to allow cell entry and improved access for engagement of Bcl-2 family members.

Antimicrobial Synergy of a Ribonuclease and a Peptide Secreted by Human Cells.

LL-37 is a secretory peptide that has antimicrobial activity. Ribonuclease 1 (RNase 1) is a secretory enzyme that is not cytotoxic. We find that human LL-37 and human RNase 1 can act synergistically to kill Gram-negative bacterial cells.

Comparative functional analysis of ribonuclease 1 homologs: molecular insights into evolving vertebrate physiology.

Pancreatic-type ribonucleases (ptRNases) comprise a class of highly conserved secretory endoribonucleases in vertebrates. The prototype of this enzyme family is ribonuclease 1 (RNase 1). Understanding the physiological roles of RNase 1 is becoming increasingly important, as engineered forms of the enzyme progress through clinical trials as chemotherapeutic agents for cancer.

Human Cancer Antigen Globo H Is a Cell-Surface Ligand for Human Ribonuclease 1.

Pancreatic-type ribonucleases are secretory enzymes that catalyze the cleavage of RNA. Recent efforts have endowed the homologues from cow (RNase A) and human (RNase 1) with toxicity for cancer cells, leading to a clinical trial. The basis for the selective toxicity of ribonuclease variants for cancerous versus noncancerous cells has, however, been unclear.

α/β-Peptide Foldamers Targeting Intracellular Protein-Protein Interactions with Activity in Living Cells.

Peptides can be developed as effective antagonists of protein-protein interactions, but conventional peptides (i.e., oligomers of l-α-amino acids) suffer from significant limitations in vivo.

Affinity of monoclonal antibodies for Globo-series glycans.

Globo-series glycans are human cell-surface carbohydrates that include stem-cell marker SSEA-4 and cancer-cell antigen Globo H. These two hexasaccharides differ only in their terminal saccharide: N-acetylneuraminic acid in SSEA-4 and L-fucose in Globo H. Herein, we evaluated the affinity of the monoclonal antibodies α-SSEA-4 and α-GH for the glycans SSEA-4 and Globo H.

Bovine brain ribonuclease is the functional homolog of human ribonuclease 1.

Mounting evidence suggests that human pancreatic ribonuclease (RNase 1) plays important roles in vivo, ranging from regulating blood clotting and inflammation to directly counteracting tumorigenic cells. Understanding these putative roles has been pursued with continual comparisons of human RNase 1 to bovine RNase A, an enzyme that appears to function primarily in the ruminant gut. Our results imply a different physiology for human RNase 1.

Assignments of RNase A by ADAPT-NMR and enhancer.

We report here backbone (1)H and (15)N assignments for ribonuclease A obtained by using ADAPT-NMR, a fully-automated approach for combined data collection, spectral analysis and resonance assignment. ADAPT-NMR was able to assign 98% of the resonances with 93% agreement with traditional data collection and assignment. Further refinement of the automated results with ADAPT-NMR enhancer led to complete (100%) assignments with 96% agreement with assignments by the traditional approach.

Contribution of electrostatics to the binding of pancreatic-type ribonucleases to membranes.

Pancreatic-type ribonucleases show clinical promise as chemotherapeutic agents but are limited in efficacy by the inefficiency of their uptake by human cells. Cellular uptake can be increased by the addition of positive charges to the surface of ribonucleases, either by site-directed mutagenesis or by chemical modification. This observation has led to the hypothesis that ribonuclease uptake by cells depends on electrostatics.

Rational design and evaluation of mammalian ribonuclease cytotoxins.

Mammalian pancreatic-type ribonucleases (ptRNases) comprise an enzyme family that is remarkably well suited for therapeutic exploitation. ptRNases are robust and prodigious catalysts of RNA cleavage that can naturally access the cytosol. Instilling cytotoxic activity requires endowing them with the ability to evade a cytosolic inhibitor protein while retaining other key attributes.