Peptides and peptidomimetics
represent the middle space between
small molecules and large proteinsthey retain the relatively
small size and synthetic accessibility of small molecules while providing
high binding specificity for biomolecular partners typically observed
with proteins. During the course of our efforts to target intracellular
protein–protein interactions in cancer, we observed that the
cellular uptake of peptides is critically determined by the cell linespecifically,
we noted that peptides show better uptake in cancer cells with enhanced
macropinocytic indices. Here, we describe the results of our analysis
of cellular penetration by different classes of conformationally stabilized
peptides. We tested the uptake of linear peptides, peptide macrocycles,
stabilized helices, β-hairpin peptides, and cross-linked helix
dimers in 11 different cell lines. Efficient uptake of these conformationally
defined constructs directly correlated with the macropinocytic activity
of each cell line: high uptake of compounds was observed in cells
with mutations in certain signaling pathways. Significantly, the study
shows that constrained peptides follow the same uptake mechanism as
proteins in macropinocytic cells, but unlike proteins, peptide mimics
can be readily designed to resist denaturation and proteolytic degradation.
Our findings expand the current understanding of cellular uptake in
cancer cells by designed peptidomimetics and suggest that cancer cells
with certain mutations are suitable mediums for the study of biological
pathways with peptide leads.
Nucleic acid modulation by small molecules is an essential process across the kingdoms of life. Targeting nucleic acids with small molecules represents a significant challenge at the forefront of chemical biology. Nucleic acid junctions are ubiquitous structural motifs in nature and in designed materials. Herein, we describe a new class of structure specific nucleic acid junction stabilizers based on a triptycene scaffold. Triptycenes provide significant stabilization of DNA and RNA three-way junctions, providing a new scaffold for building nucleic acid junction binders with enhanced recognition properties. Additionally, we report cytotoxicity and cell uptake data in two human ovarian carcinoma cell lines.
One of the most challenging goals of modern synthetic chemistry is to develop multi-step reactions for rapid and efficient access to complex molecules. We report a triple aryne-tetrazine reaction that enables rapid access to a new class of polyaromatic heterocycles. This new reaction, which couples diverse reactivity modes between simple aryne and tetrazine starting materials, proceeds in a single operation and takes less than 5 minutes in air with no metal catalyst.
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