Tetrazole analogues of cyclolinopeptide A: synthesis, conformation, and biology.
Linear and cyclic analogues of cyclolinopeptide A (CLA) with two dipeptide segments (Val(5)-Pro(6) and Pro(6)-Pro(7)) replaced by their tetrazole derivatives were synthesized by the SPPS technique and cyclized using TBTU (O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate) reagent. The conformational properties of the c(Leu(1)-Ile(2)-Ile(3)-Leu(4)-Val(5)-Pro(6)-psi[CN(4)]-Ala(7)-Phe(8)-Phe(9)) were investigated by NMR and computational techniques. The overall solution structure of this cyclic peptide resembles that observed for the CLA in the solid state. These studies of cyclic tetrazole CLA analogue confirm that the 1,5-disubstituted tetrazole ring functions as an effective, well-tolerated cis-amide bond mimic in solution. The peptides were examined for their immunosuppressive activity in the humoral response test. For cyclic analogues the immunosuppressive activity, at low doses, is equal in magnitude to the activity presented by cyclosporin A and native CLA. The conformational and biological data seem indicate that the Pro-Pro-Phe-Phe moiety and the preservation of the CLA backbone conformation are important for immunosuppressive activity.
Kaczmarek
Krzysztof
K
Institute of Organic Chemistry, Technical University, 90-924 Łódź, Poland.
Jankowski
Stefan
S
Siemion
Ignacy Z
IZ
Wieczorek
Zbigniew
Z
Benedetti
Ettore
E
Di Lello
Paola
P
Isernia
Carla
C
Saviano
Michele
M
Zabrocki
Janusz
J
D000595:Amino Acid Sequence; D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008968:Molecular Conformation; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000737:chemistry* / Q000494:pharmacology
D007166:Immunosuppressive Agents; D010456:Peptides, Cyclic; D013777:Tetrazoles; C055018:cyclolinopeptide A