Structural effects in aza-peptide bond formation reaction
Date
2023-05-26
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Abstract
Asa-peptiidid on peptiidi analoogid, mis lagunevad elusorganismis aeglasemalt ja on seetõttu paljulubavad ravimikandidaadid. Nende bioaktiivsete omaduste laiemat uurimist takistavad aga asa-peptiidsideme sünteesil ilmnevad probleemid, eelkõige madal saagis ja aeglane reaktsioon. Reaktsiooni kineetiliste parameetrite määramine on üheks võimaluseks eksperimentaalselt hinnata amino- ja asa-aminohapete N-terminaalse aminorühma reaktsioonivõime erinevust ning uurida tahkefaasi peptiidsünteesi protokolli sobivust asa-peptiidsideme moodustamiseks. Tulemustest selgus, et tavalist tahkefaasi peptiidsünteesi protokolli ei saa rakendada otseselt asa-peptiidsünteesis. Asa-peptiidsideme reaktsiooni mõjutavad nii kasutatava aktivaatori efektiivsus kui ka aminohappe ja asa-aminohappe kõrvalahela steeriline efekt. Seega on vajalik asa-peptiidide sünteesimeetodeid arendada suunas, mis võimaldaks asa-aminohappe N-terminaali efektiivsemat atsüülimist. See on oluline automatiseeritud asa-peptiidide sünteesimeetodite loomiseks, mis omakorda annaks võimaluse nende ühendite bioaktiivsuse laiaulatuslikumateks uuringuteks.
Aza-peptides are peptide analogues that degrade more slowly in the living organisms and are therefore promising drug candidates. However, the problems encountered in the synthesis of the aza-peptide bond, especially the low yield and slow reaction, hinder the wider investigation of their bioactive properties. Determining the kinetic parameters of the reaction is one way to experimentally evaluate the difference in the reactivity of the N-terminal amino group of amino and aza-amino acids and to study the suitability of the solid-phase peptide synthesis protocol for aza-peptide bond formation. Performed kinetic studies showed that standard solid-phase peptide synthesis protocol cannot be applied directly to aza-peptide synthesis. The reaction of the aza-peptide bond is influenced by the effectiveness of the activator used as well as the steric effect of the side chain of the amino acid and the aza-amino acid. Therefore, it is necessary to develop the synthesis methods for aza-peptides in a direction that would enable more effective acylation of the N-terminal of the aza-amino acid. This is important for the creation of automated aza-peptide synthesis methods, which in turn would provide an opportunity for more comprehensive studies of the bioactivity of these compounds.
Aza-peptides are peptide analogues that degrade more slowly in the living organisms and are therefore promising drug candidates. However, the problems encountered in the synthesis of the aza-peptide bond, especially the low yield and slow reaction, hinder the wider investigation of their bioactive properties. Determining the kinetic parameters of the reaction is one way to experimentally evaluate the difference in the reactivity of the N-terminal amino group of amino and aza-amino acids and to study the suitability of the solid-phase peptide synthesis protocol for aza-peptide bond formation. Performed kinetic studies showed that standard solid-phase peptide synthesis protocol cannot be applied directly to aza-peptide synthesis. The reaction of the aza-peptide bond is influenced by the effectiveness of the activator used as well as the steric effect of the side chain of the amino acid and the aza-amino acid. Therefore, it is necessary to develop the synthesis methods for aza-peptides in a direction that would enable more effective acylation of the N-terminal of the aza-amino acid. This is important for the creation of automated aza-peptide synthesis methods, which in turn would provide an opportunity for more comprehensive studies of the bioactivity of these compounds.
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Väitekirja elektrooniline versioon ei sisalda publikatsioone
Keywords
peptide bond synthesis, acylation, chemical synthesis