PROPERTIES OF CONSTRAINED CYCLIC PSEUDOPEPTIDES

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Pseudopeptides with a wide variety of amide bond replacements (psi[CH(2)S], psi[CH(2)SO], psi[CH(2)NH], psi[CH(2)NH(2)], psi[CH(2)SO(2)], and psi[CSNH]) have been shown to possess a diverse set of physical, structural, and conformational properties. When judiciously chosen, the correct surrogate can provide peptide analogs with increased stability , improved potency, optimized solubility, oral activity, and, sometimes, enhanced selectivity or even antagonist properties. In this renewal we propose to exploit the advantages of one property that is often a detriment of many of our examined replacements, namely, increased flexibility. Both linear and cyclic pseudopeptide analogs will prepared and thoroughly characterized. Among specific objectives are: 1) the preparation of analogs with multiple amide replacements. These will be engineered to provide improved H-bonding for increased intramolecular stabilization, e.g., using an improved donor (CH(2)NH(2)) and an improved acceptor (CH(2)SO) to stabilize a beta-turn or helix; 2) the concept of pseudopeptide "induced fit" will be explored by the conjunction of backbone modifications designed to protect against enzyme breakdown along with conformational constraints intended to provide optimized binding and selectivity: target analogs are initially sought as farnesyl transferase inhibitors. Selective inhibitors of prenylation could have widespread biochemical and therapeutic potential; 3) selected examples of small ring biologically active peptides will be used to apply the findings from our conformational studies on cyclic pseudopeptides. For example, the recently isolated endothelin antagonist cyclo[D-Val-L-Leu-D-Trp-D-Glu-L- Ala] will be used as a host for a variety of amide acid and surrogate replacements designed to stabilize proposed beta and gamma turns. These compounds will be assayed both in vitro and in vivo for potential antihypertensive activities. Finally, we propose to expand our synthetic routes to include more examples of tri- and tetrafunctional psi[CH(2)S] pseudodipeptides. These will be used to prepare novel macrocyles, as well as linear Arg-Arg surrogates. Their behavior toward specific proteolytic enzymes will be assayed using reversed phase chromatography.