Peptides containing one or more backbone modifications often have improved stability toward proteolytic degradation, and diverse conformational, electronic, and solubility properties. We propose to continue our systematic evaluation of the conformational properties of model cyclic pseudopeptides, evaluate new synthetic procedures for their preparation, and investigate the biological consequences of amide bond replacements in several small cyclic bioactive parents, including cyclo (Pro-Phe-Met-Gly-D-Trp-Met), a recently described CCK analog with selective central receptor affinity, in small, potent, somatostatin analogs, and later in other appropriate hosts. Modified cyclic pseudopeptides represent potentially useful species for new peptide-based drug candidates as well as for selective enzyme inhibitors. But these compounds also provide an alternative approach for novel macrocycle preparation with stereochemically defined side chain constituents. The macrocycles to be prepared will incorporate psi(CH2S), psi(CH2NH), and psi(CSNH) amide surrogates, and side chain functionalities will include both acidic and basic constituents. Following complete structural and conformational characterization, the possibility of selective ion coordination or customized catalytic activity will also be investigated. The hypothesis that effective enzyme mimetics may be best fashioned from a combination of amino acid and modified amino acid structures will be a central theme of our experimental approach.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM033376-06
Application #
3283045
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1985-04-01
Project End
1993-03-30
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
6
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Louisville
Department
Type
Schools of Arts and Sciences
DUNS #
City
Louisville
State
KY
Country
United States
Zip Code
40292
Burden, John E; Davis, Peg; Porreca, Frank et al. (2002) Synthesis and biological activities of YkFA analogues: effects of position 4 substitutions and altered ring size on in vitro opioid activity. Bioorg Med Chem Lett 12:213-6
Burden, J E; Davis, P; Porreca, F et al. (1999) Synthesis and biological activities of position one and three transposed analogs of the opioid peptide YKFA. Bioorg Med Chem Lett 9:3441-6
Romanovskis, P; Spatola, A F (1998) Preparation of head-to-tail cyclic peptides via side-chain attachment: implications for library synthesis. J Pept Res 52:356-74
Crozet, Y; Wen, J J; Loo, R O et al. (1997) Synthesis and characterization of cyclic pseudopeptide libraries containing thiomethylene and thiomethylene-sulfoxide amide bond surrogates. Mol Divers 3:261-76
Wen, J J; Spatola, A F (1997) A systematic approach to the solid-phase synthesis of linear and cyclic pseudopeptide libraries containing psi[CH2NH] amide bond surrogates. J Pept Res 49:3-14
Spatola, A F; Crozet, Y (1996) Rediscovering an endothelin antagonist (BQ-123): a self-deconvoluting cyclic pentapeptide library. J Med Chem 39:3842-6
Ma, S; Richardson, J F; Spatola, A F (1993) Crystal structures of two cyclic pseudopentapeptides containing psi[CH2S] and psi[CH2SO] backbone surrogates. Biopolymers 33:1101-10
Ma, S; Spatola, A F (1993) Conformations of psi [CH2NH] pseudopeptides. Cyclo[Gly-Pro psi [CH2NH]Gly-D-Phe-Pro]-TFA and cyclo[Gly-Pro psi [CH2NH]Gly-D-Phe-Pro] Int J Pept Protein Res 41:204-6
Spatola, A F; Anwer, M K; Rao, M N (1992) Phase transfer catalysis in solid phase peptide synthesis. Preparation of cyclo[Xxx-Pro-Gly-Yyy-Pro-Gly] model peptides and their conformational analysis. Int J Pept Protein Res 40:322-32
Grzonka, Z; Kasprzykowski, F; Lubkowska, L et al. (1991) In vitro degradation of some arginine-vasopressin analogs by homogenates of rat kidney, liver and serum. Pept Res 4:270-4

Showing the most recent 10 out of 18 publications