Conformational mimicry: Synthesis and solution conformation of a cyclic somatostatin hexapeptide containing a tetrazole cis amide bond surrogate

Abstract

Potent, cyclic hexapeptide analogues of somatostatin are generally believed to adopt some common secondary structural features: a II' beta turn at one end of the cycle, and a type VI turn with a cis amide bond at the other. A proposed cis amide surrogate, the 1,5-disubstituted tetrazole, has been placed into a cyclic hexapeptide analog of somatostatin in order to constrain the putative cis amide bond. The final cyclization was done by either chemical or enzymatic means. The product, cyclo(Ala6-Tyr7-D-Trp8-Lys9-Val10-Phe11-psi[CN4] ), was found to have 83% of the activity of somatostatin. Solution nmr analysis in DMSO/water revealed that the backbone as well as side chain chi1 and chi2 were well ordered. Relaxation matrix methods were used to extract distance restraints from the nuclear Overhauser effect spectroscopy data set, and these were used in a systematic search of torsional space to identify structures consistent with the nmr data. Restrained minimizations of these structures using a number of different force fields produced structures having the expected beta II' turn at D-Trp8-Lys9 and a beta VIa turn in the Phe11-psi[CN4]-Ala6 portion of the molecule. The similarity of the minimized structures to those previously reported for cyclic hexapeptide analogues of somatostatin confirms the similarity of the tetrazole geometry to that of the cis amide in solution.

Back to the future: Ribonuclease A

“…19 The discussion centered on generating a construct similar to RNase S, but which explored the role of the C-terminal segment of RNase contributing His119 to the catalytic site. Ultimately, the semisynthetic ribonuclease, RNase-(1-118)- (111)(112)(113)(114)(115)(116)(117)(118)(119)(120)(121)(122)(123)(124), was evolved to study the role of the C-terminal segment in recognition and catalysis. [45][46][47][48] A three-component system, combining equimolar amounts of RNase fragments 1-20, 21-118, and 111-124, retained 30% of the enzymatic activity of intact RNase.…”

“…Other proline analogs impact cis-trans amide isomerization and, therefore, type-VI reverse-turn formation. 118,122 An excellent geometrical mimic of the cis-amide bond, the 1,5-disubstituted tetrazole ring, has been used by Zabrocki and coworkers [123][124][125] to probe type-VI reverse-turn recognition. Incorporation of a series of such …”

Heterocyclic-based peptidomimetics

“…Subsequent work by Zabrocki et al [13] extended this study to the stereoselective synthesis of the tetrazole mimetic with the inclusion of quinine in the reaction conditions. This methodology has been used to probe the importance of a cis peptide bond geometry in a number of systems [7] including Thyroliberin (TRH), Bradykinin, Cholecystokinin and Somatostatin (for example see 5b [14] where a tetrazole has been incorporated into the -Phe-N-methyl-Ala-amide bond of the potent Somatostatin analogue 5a, Figure 1).…”

Tetrazole peptides as copper(II) ion chelators

“…The aim of reviewed studies was to investigate the coordinating effects of a new class of peptide chelators, tetrazole opioid peptide analogues [15][16][17][18][19][20][21][22], on copper(II) ions. The 1,5-disubstituted tetrazole ring is a cis amide bond surrogate [23][24][25][26]. Enkephalins and ␤-casomorphin-7 were subjected to tetrazole modification.…”