Peptide and polypeptide drugs such as interferons, immunoconjugates, tissue plasminogen activator, human growth hormone and erythropoeitin, made available by the biotechnological revolution, are now entering the marketplace and presenting pharmaceutical science with challenges in drug stability and delivery that range from basic science to developmental technology. This proposal links the practical problem of peptide and protein formulation in polymer matrices for controlled-release applications to the basic mechanistic science involved in degradation reactions in these unusual media. In the first grant period the research has addressed the influence of polymer matrix incorporation on deamidation at Asn """"""""hot spots"""""""", one of the most common routes of degradation of peptide and protein pharmaceuticals. Studies proposed for this competing continuation will extend this research to address the effects of peptide and protein secondary structure on deamidation in polymers. In addition, since the findings to date suggest that interactions with polymers may stabilize peptides against deamidation in the solid state, the proposed studies will investigate deamidation of charged peptides in hydrated solid formulations containing ionizable polymers, a system in which stabilization by ionic interactions is anticipated. Finally, the proposed studies will examine the effect of polymer matrix incorporation on oxidation reactions of peptides and proteins, a second class of degradation reaction of considerable practical importance in protein formulation. The principal investigator's experience in the development and characterization of polymeric drug delivery systems will be supplemented by collaborators and co-investigators with expertise in the deamidation and oxidation of peptides and proteins in solution and solid phases, in mechanistic bioorganic chemistry, in the biophysical characterization of protein structure and interactions, and in theoretical approaches to reactivity in solution and solid states.
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| D'Souza, Ajit Joseph M; Schowen, Richard L; Topp, Elizabeth M (2004) Polyvinylpyrrolidone-drug conjugate: synthesis and release mechanism. J Control Release 94:91-100 |
| Stotz, C E; Borchardt, R T; Middaugh, C R et al. (2004) Secondary structure of a dynamic type I'beta-hairpin peptide. J Pept Res 63:371-82 |
| Li, Bei; Borchardt, Ronald T; Topp, Elizabeth M et al. (2003) Racemization of an asparagine residue during peptide deamidation. J Am Chem Soc 125:11486-7 |
| D'Souza, Ajit Joseph M; Schowen, Richard L; Borchardt, Ronald T et al. (2003) Reaction of a peptide with polyvinylpyrrolidone in the solid state. J Pharm Sci 92:585-93 |
| Li, R; Hageman, M J; Topp, E M (2002) Effect of viscosity on the deamidation rate of a model Asn-hexapeptide. J Pept Res 59:211-20 |
| Song, Y; Schowen, R L; Borchardt, R T et al. (2001) Effect of 'pH' on the rate of asparagine deamidation in polymeric formulations: 'pH'-rate profile. J Pharm Sci 90:141-56 |
| Song, Y; Schowen, R L; Borchardt, R T et al. (2001) Formaldehyde production by Tris buffer in peptide formulations at elevated temperature. J Pharm Sci 90:1198-203 |
| Goolcharran, C; Stauffer, L L; Cleland, J L et al. (2000) The effects of a histidine residue on the C-terminal side of an asparaginyl residue on the rate of deamidation using model pentapeptides. J Pharm Sci 89:818-25 |
| Xie, M; Aube, J; Borchardt, R T et al. (2000) Reactivity toward deamidation of asparagine residues in beta-turn structures. J Pept Res 56:165-71 |
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