The essential amino acid Histidine (His, H), first isolated in 1896 by Albrecht Kossel and Sven Gustaf Hedin, bears an imidazole side chain which plays a crucial role for the activity of many enzymes. It can act as a proton shuttle and with its two N-donors it is one of the most effective ligation sites in metallopeptides.

An example for an essential histidine-bearing peptide is the glucagon-like peptide-1 (GLP-1), which controls the secretion of insulin in a glucose-dependent manner. Truncation studies on its sequence revealed the importance of the histidine residue at position 7 for receptor recognition, function, and the peptide’s insulinotropic activity. As native GLP-1 is rapidly degraded, the modified analogues Liraglutide and Semaglutide – also bearing this histidine residue – represent essential treatments for type 2 diabetes.

Sequence of the glucagon-like peptide-1 (7-37) amide:

H-His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly-NH₂

Iris Biotech offers a selection of deamino- and decarboxy-histidine derivatives, which can be used as tools for the preparation of libraries to investigate structure activity relationships leading to the generation of drugs with improved pharmacokinetics. As especially histidines are prone to racemization during peptide synthesis, the installation of deamino- or decarboxy-His at the C- or N-terminus of a peptide brings another crucial advantage as it allows to circumvent this issue due to the lack of chirality. Thus, this measure reduces the amount of undesired side-products, which might be difficult to remove.

For deamino-histidines, Iris Biotech provides the trityl protected imidazole propionic acid HAA6170, its shorter chain imidazole-4-acetic acid HAA9175 and the demethylated derivative thereof (HAA9180). HAA9175 is reported as building block for the synthesis of imidazolyl-polyethyleneimine modified nanoparticles benefiting from increased transfection efficiency as well as for the synthesis of ribonuclease mimics. Furthermore, imidazole-4-acetic acid is suggested as antagonist of GABA_C receptors and partial GABA_AR agonist being capable of penetrating the blood-brain barrier in vivo.

Decarboxy-histidine HAA9185 represents a trityl protected histamine and is reported as component of potent agonists of the histamine H₂ and H₄ receptor. It can be placed at the C-terminus of a peptide replacing natural histidine and is reported within the synthesis of truncated GLP-1 based peptides to analyze metabolic stability and pharmacokinetic properties. Other reports highlight HAA9185 as building block for potent inhibitors of farnesyltransferase and geranylgeranyltransferase-I. Its longer chain derivative HAA9190 is highlighted as fragment of selective H₂R and H₄R agonists and for its inhibitory activity towards the H₃ receptor and the histamine N-methyltransferase.

References:

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