Helialasid

Helialasid is a class of synthetic small molecules proposed to stabilize alpha-helical structures in peptides and proteins. The name blends "helix" with "acid," reflecting the proposed role of these compounds as backbone-stabilizing agents that can donate or accept hydrogen bonds to support helical conformations. In protein engineering literature, helialasids are discussed as tools to increase helicity in short or marginally helical sequences.

First described in theoretical and experimental studies in the late 2000s, prototypes of helialasid were reported by researchers at the Helicity Institute and collaborating labs. Subsequent work identified several derivatives with improved solubility and selective affinity for peptide backbones, enabling modest increases in helicity in model peptides.

Chemical characteristics include a rigid core, often lactam- or heterocyclic-based, bearing hydrogen-bond donor and acceptor moieties and an amphiphilic side chain that enhances membrane permeability. These features are intended to enable both interaction with the peptide backbone and cell- or organelle-access when used in biological contexts.

Helialasid is believed to stabilize alpha-helices by preferentially aligning and donating hydrogen bonds to backbone amide groups at i and i+4 positions, reducing the entropic penalty of helix formation. Some derivatives form transient intramolecular backbones that mimic the i to i+4 hydrogen bonding network.

Applications include stabilization of therapeutic helical peptides, design of inhibitors targeting helix-mediated protein–protein interactions, and incorporation into stapled peptide frameworks to improve biophysical properties such as proteolytic resistance and cellular uptake. The approach is considered complementary to existing helix-stabilizing strategies and is the subject of ongoing research.

Limitations and status: solubility, off-target interactions, and potential cytotoxicity limit practical use in complex biological systems. To date, there is no consensus on in vivo efficacy or safety, and no regulatory approvals exist. Research continues to refine derivatives and explore broader applications in protein engineering and drug design.

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