Fixierung cyclischer Peptide: Mimetika von Proteinstrukturmotiven

Abstract

Viele Proteine entfalten ihre biologische Aktivität über kleine exponierte Oberflächenregionen aus gefalteten Peptiden mit wohldefinierten dreidimensionalen Strukturen, Epitope genannt. Kurze synthetische Peptidsequenzen, die diesen bioaktiven Proteinoberflächen entsprechen, bilden in Wasser keine thermodynamisch stabilen proteinähnlichen Strukturen. Die Bildung proteinähnlicher biologisch aktiver Konformationen (Stränge, Helices, Kehren) kann jedoch durch Cyclisierung in Verbindung mit anderen molekularen Verstrebungen induziert werden. Letztere helfen bei der Feinabstimmung der dreidimensionalen Struktur. Solche fixierten cyclischen Peptide können ähnliche biologische Aktivitäten und Wirkungen wie das als Vorbild dienende Protein haben, sodass sie als biologische Sonden und Leitstrukturen für Therapeutika, Diagnostika und Impfstoffe dienen können. Dieser Aufsatz beleuchtet Beispiele für cyclische Peptide, die dreidimensionale Strukturen von Strang‐, Kehren‐ oder Helixabschnitten von Peptiden und Proteinen nachahmen und beschreibt einige weitere Elemente, die in cyclisch peptidischen Naturstoffen und synthetischen makrocyclischen Peptidomimetika vorkommen, dort die Peptidstruktur verfeinern und ihr biologische Aktivitäten verleihen.

The Synthesis of Structurally Diverse Macrocycles By Successive Ring Expansion

“…peptidomimetics. [1,26,27] Finally,the synthesis of cyclic lactone 17 o from b-ketoester 12 f and benzyl-protected alcohol derivative 13 j indicates that SuRE is not limited to amino acid derived linear fragments. [28] As with the Cbz-protected variant, hydrogenolysis was used to promote benzyl group cleavage and ring expansion in situ.…”

“…Using the SuRE synthetic method, diverse families of macrocycles should be accessible more easily than is possible using existing methods,a nd because there is no discrete macrocyclization step,t heir syntheses should be viable on al arge scale.T he freedom to install precise sequences of functional groups into macrocycles is likely to be of value in the design and development of many such applications in the various research fields highlighted above. [1][2][3][4][5][6][7][8][26][27][28] Future work will explore these possibilities,a s well as further expanding the substrate scope and challenging the methodology to create even larger,m ore complex macrocycles.…”

Solution and solid state conformational preferences of a family of cyclic disulphide bridged tetrapeptides

“…Small peptides mimicking the biologically significant motifs can be very useful model systems to investigate and understand structures, conformations and dynamics of biologically relevant peptides . More recently, small peptides and peptidomimetics themselves gained significant attention due to their potential biological application especially as therapeutic agents . However, a major goal remains the design and preparation of stable and biological active small peptides and peptidomimetics, which overcome current limitations such as fast proteolysis, low membrane permeability, poor oral bioavailability, or a lack of (conformational) stability due to high flexibility …”

The Synthesis of Structurally Diverse Macrocycles By Successive Ring Expansion

“…Chemie peptidomimetics. [1,26,27] Finally,the synthesis of cyclic lactone 17 o from b-ketoester 12 f and benzyl-protected alcohol derivative 13 j indicates that SuRE is not limited to amino acid derived linear fragments. [28] As with the Cbz-protected variant, hydrogenolysis was used to promote benzyl group cleavage and ring expansion in situ.…”