Abstract: Novel peptides which are conformationally constrained backbone cyclized somatostatin analogs, having somatostatin receptor subtype selectivity are disclosed. These patterns or receptor subtype selectivity provide compounds having improved therapeutic utility. Methods for synthesizing the somatostatin analogs and for screening of the somatostatin analogs are also disclosed. Furthermore, pharmaceutical compositions comprising somatostatin analogs, and methods of using such compositions are disclosed.

Abstract: Methods of use of pharmaceutical compositions and novel peptides which are conformationally constrained backbone cyclized somatostatin analogs, having somatostatin receptor subtype selectivity, are disclosed. These patterns or receptor subtype selectivity provide compounds having improved therapeutic utility. Methods for synthesizing the somatostatin analogs and for screening of the somatostatin analogs are also disclosed. Furthermore, pharmaceutical compositions comprising somatostatin analogs are disclosed.

Abstract: The design and the synthesis of backbone cyclic peptide analogs which functionally mimic the nuclear localization signal (NLS) region of macromolecules is disclosed. The principles of the invention are exemplified for the NLS sequences of the human immunodeficiency virus type 1 proteins MA, Vpr, Tat and NLS-like sequences of HIV-1 protein Vif. We disclose the discovery of a novel, highly potent backbone cyclic peptide, designated BCvir, which inhibits nuclear import with an IC50 value of 35 nM. This inhibitory potency is to be compared to 12 &mgr;M exhibited by the linear parent HIV-1 MA NLS peptide. BCvir also reduced HIV-1 production by 75% in infected non-dividing cultured human T-cells and was relatively resistant to tryptic digestion. These properties render backbone cyclic peptide analogs of NLS or NLS-like sequences as candidates for novel drugs based on blocking nuclear import of viral genomes.

Abstract: A process is disclosed for using triphosgene as an efficient and effective coupling reagent during peptide synthesis, by in situ generation of amino acid chloride from a protected amino acid. This process is particularly useful for the coupling to sterically hindered amino acid residues, or for other difficult couplings. Furthermore, the same reagent can be used for the derivatization of peptides by formation of an amide bond between a free amine on a peptide and a carboxylic acid, or for the coupling of an amino acid to a solid support.

Abstract: A process is disclosed for using triphosgene as an efficient and effective coupling reagent during peptide synthesis, by in situ generation of amino acid chloride from a protected amino acid. This process is particularly useful for the coupling to sterically hindered amino acid residues, or for other difficult couplings. Furthermore, the same reagent can be used for the derivatization of peptides by formation of an amide bond between a free amine on a peptide and a carboxylic acid, or for the coupling of an amino acid to a solid support.

Abstract: A method for constructing a potentially pharmaceutically useful molecule that displays a predefined pharmacophore associated with a desired biological activity is disclosed. The pharmacophore is first used to screen a virtual library of scaffolds, described by three-dimensional coordinates, in order to identify one or more scaffold(s) which could potentially display substituents that alone or together with scaffold atoms comprise a pharmacophore. The screening process involves first placing rotamers from a virtual library of substituents onto each attachment point of each scaffold, and then examining the resultant Virtual Combinatorial Library (VCL) according to one or more parameters required by the pharmacophore.

Abstract: Novel backbone cyclized peptide analogs are formed by means of bridging groups attached via the alpha nitrogens of amino acid derivatives to provide novel non-peptidic linkages. Novel building units disclosed are N.sup..alpha. (.omega.-functionalized) amino acids constructed to include a spacer and a terminal functional group. One or more of these N.sup..alpha. (.omega.-functionalized) amino acids are incorporated into a peptide sequence, preferably during solid phase peptide synthesis. The reactive terminal functional groups are protected by specific protecting groups that can be selectively removed to effect either backbone-to-backbone or backbone-to-side chain cyclizations. The invention is exemplified by backbone cyclized bradykinin antagonists having biological activity. Further embodiments of the invention are somatostatin analogs having one or two ring structures involving backbone cyclization.

Abstract: Novel backbone cyclized peptide analogs are formed by means of bridging groups attached via the alpha nitrogens of amino acid derivatives to provide novel non-peptidic linkages. Novel building units disclosed are N.sup..alpha. (.omega.-functionalized)amino acids constructed to include a spacer and a terminal functional group. One or more of these N.sup..alpha. (.omega.-functionalized) amino acids are incorporated into a peptide sequence, preferably during solid phase peptide synthesis. The reactive terminal functional groups are protected by specific protecting groups that can be selectively removed to effect either backbone-to-backbone or backbone-to-side chain cyclizations. The invention is exemplified by backbone cyclized bradykinin antagonists having biological activity. Further embodiments of the invention are somatostatin analogs having one or two ring structures involving backbone cyclization.