title: Intramolecular azo-bridge as a cystine disulfide bond surrogate: Somatostatin-14 and brain natriuretic peptide (BNP) analogs.
abstract: Cystine disulfide bond is a common feature in numerous biologically active peptides and proteins and accordingly its replacement by various surrogates presents a potential route to obtain analogs with improved pharmacokinetic characteristics. The purpose of the present study was to assess whether an azo-bridge can serve as such a surrogate. In view of the marked clinical significance of somatostatin and the brain natriuretic peptide (BNP) we choose these peptides as a model. Three cyclic-azo somatostatin analogs and three cyclic-azo BNP analogs were effectively prepared in solution through azo bond formation between p-amino phenylalanine and His or Tyr residues that were positioned in the peptide sequences in place of the native Cys residues. The peptides binding affinities to the sst₂ and ANP-receptor (NPR-A) expressed on rat acinar pancreating carcinoma AR4-2J cell membranes and HeLa cells, respectively, were examined. The somatostatin analogs displayed good to moderate affinities to the rat sst₂ in the nM range with best results obtained with peptide 2, that is, IC₅₀ = 8.1 nM. Molecular dynamics simulations on these peptides suggests on a correlation between the observed binding potencies and the degree of conformational space overlapping with that of somatostatin. The BNP analogs exhibited binding affinities to the NPR-A in the nM range with best results obtained with BNP-1, that is, IC₅₀ = 60 nM.
authors.affiliation: Department of Chemical Biology, The Weizmann Institute of Science, Rehovot, Israel. gilf@iibr.gov.il
authors.forename: Gil
authors.initials: G
authors.lastname: Fridkin
authors.forename: Theodosia
authors.initials: T
authors.lastname: Maina
authors.forename: Berthold A
authors.initials: BA
authors.lastname: Nock
authors.forename: Dan
authors.initials: D
authors.lastname: Blat
authors.forename: Vered
authors.initials: V
authors.lastname: Lev-Goldman
authors.forename: Yosef
authors.initials: Y
authors.lastname: Scolnik
authors.forename: Aviva
authors.initials: A
authors.lastname: Kapitkovski
authors.forename: Yelena
authors.initials: Y
authors.lastname: Vachutinsky
authors.forename: Yoram
authors.initials: Y
authors.lastname: Shechter
authors.forename: Yaakov
authors.initials: Y
authors.lastname: Levy
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001391:Azo Compounds / Q000737:chemistry*; D045744:Cell Line, Tumor; D003553:Cystine / Q000737:chemistry*; D004220:Disulfides / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D056004:Molecular Dynamics Simulation; D020097:Natriuretic Peptide, Brain / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism
chemical_list: D001391:Azo Compounds; D004220:Disulfides; D020097:Natriuretic Peptide, Brain; D003553:Cystine; D013004:Somatostatin