The enormous importance of peptidal hormone and neurotransmitter agonists and antagonists and of peptidal inhibitors of proteolytic enzymes is well understood. However, peptides are rapidly degraded in vivo by exo and endo peptidases. Another shortcoming of peptides as potential therapeutic agents is their lack of bioavailability by the oral route. The latter deficiency appears to be due in part to the amide backbone. We propose to synthesize novel mimics of peptide hormone agonists/antagonists which are devoid of the amide backbone. The peptide side chains are to be retained in the appropriate spatial disposition. In the case of the enzyme inhibitor mimics, provision is also made for H-bonding interactions with the enzyme backbone. Such H-bonding is not required for the interaction of hormone agonists/antagonists with their receptors. The proposed synthetic targets are designed to serve as mimics or antagonists of somatostatin, substance P, the chemotaxis-related formyl tripeptide, and the fibrinogen receptors. The proposal is also concerned with inhibitors of the proteolytic enzyme renin and other aspartate proteases, notably the HIV1 protease of importance in AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM041821-04A1
Application #
3300263
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1989-12-01
Project End
1997-07-31
Budget Start
1993-08-01
Budget End
1994-07-31
Support Year
4
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Arts and Sciences
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Smith 3rd, Amos B; Charnley, Adam K; Hirschmann, Ralph (2011) Pyrrolinone-based peptidomimetics. ""Let the enzyme or receptor be the judge"". Acc Chem Res 44:180-93
Hirschmann, Ralph F; Nicolaou, K C; Angeles, Angie R et al. (2009) The beta-D-glucose scaffold as a beta-turn mimetic. Acc Chem Res 42:1511-20
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Angeles, Angie R; Neagu, Irina; Birzin, Elizabeth T et al. (2005) Synthesis and binding affinities of novel SRIF-mimicking beta-D-glucosides satisfying the requirement for a pi-cloud at C1. Org Lett 7:1121-4
Neelamkavil, S; Mowery, B P; Thornton, E R et al. (2005) A practical synthesis of Nalpha-Fmoc-L-pyrazinylalanine via Schollkopf's chiral auxiliary. J Pept Res 65:139-42
Neelamkavil, Santhosh; Arison, Byron; Birzin, Elizabeth et al. (2005) Replacement of Phe6, Phe7, and Phe11 of D-Trp8-somatostatin-14 with L-pyrazinylalanine. Predicted and observed effects on binding affinities at hSST2 and hSST4. An unexpected effect of the chirality of Trp8 on NMR spectra in methanol. J Med Chem 48:4025-30
Abrous, Leila; Jokiel, Patrick A; Friedrich, Sarah R et al. (2004) Novel chimeric scaffolds to extend the exploration of receptor space: hybrid beta-D-glucose-benzoheterodiazepine structures for broad screening. Effect of amide alkylation on the course of cyclization reactions. J Org Chem 69:280-302
Prasad, Vidya; Birzin, Elizabeth T; McVaugh, Cheryl T et al. (2003) Effects of heterocyclic aromatic substituents on binding affinities at two distinct sites of somatostatin receptors. Correlation with the electrostatic potential of the substituents. J Med Chem 46:1858-69
Smith 3rd, Amos B; Cantin, Louis-David; Pasternak, Alexander et al. (2003) Design, synthesis, and biological evaluation of monopyrrolinone-based HIV-1 protease inhibitors. J Med Chem 46:1831-44

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