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

Denise D. Beusen, Janusz Zabrocki, Urszula Slomczynska, Richard D. Head, Jeff L.‐F Kao, Garland R. Marshall

Research output: Contribution to journalArticlepeer-review

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Abstract

Potent, cyclic hexapeptide analogues of somatostatin are generally believed to adopt some common secondary structural features: a II′ β 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‐Ψ[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 χ1 and χ2 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 βII′ turn at D‐Trp8‐Lys9 and αβVIa turn in the Phe11‐Ψ[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. © 1995 John Wiley & Sons, Inc.

Original languageEnglish
Pages (from-to)181-200
Number of pages20
JournalBiopolymers
Volume36
Issue number2
DOIs
StatePublished - Aug 1995

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