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Dr Patrick Perlmutter
School of Chemistry
Monash University
PO Box 23, Victoria, 3800
Email: patrick.perlmutter@sci.monash.edu.au
Tel: +61-3-9905 4522
Fax: +61-3-9905 4597

Therapeutic Peptidase Inhibitors
The action of most neuropeptides is terminated by specific extracellular peptidases and these enzymes therefore play an important role in the regulation of the function of the central nervous system. The availability of inhibitors of these enzymes is important for characterising the role of these enzymes in peptide signalling in the brain and ultimately for the development of new therapeutic agents for the treatment of cardiovascular disease. In collaboration with Assoc. Prof. Marie-Isabel Aguilar (Department of Biochemistry & Molecular Biology) and Dr Ian Smith (Baker Heart Research Institute) we have focussed on a family of peptidases associated primarily with cardiovascular function including angiotensin converting enzyme (ACE), angiotensin converting enzyme-2 (ACE2), aminopeptidase P (APP), thimet oligopeptidase (EP 24.15) and neurolysin (EP24.16). This successful collaboration with Assoc. Profs. Aguilar and Smith has led to the development of new enantioselective methods for the synthesis of cyclic and acyclic b-amino acids as well as a number of studies on their use for the design of enzyme inhibitors with potential cardiovascular applications. The resulting publications were the first studies to demonstrate that b-amino acids could be used to convert peptide substrates into proteolytically-resistant enzyme inhibitors.
Lew R A, Boulos, E, Stewart K M, Perlmutter P, Harte M, Bond S, Aguilar M I, Smith A I, `Bradykinin analogues with b-amino acid substitutions reveal subtle differences in substrate specificity between the endopeptidases EC and EC’, J Pept Sci, 6 (2000) 440-445.

Lew R A, Boulos, E, Stewart K M, Perlmutter P, Harte M, Bond S, Gerryn, S, Norman, M U, Lew M J, Aguilar M I, Smith A I, `Substrate Analogs Incorporating b-Amino Acids: Potential Use in Peptidase Inhibition’, FASEB J. 15 (2001) 351-356.

Steer D L, Lew R, Perlmutter P, Smith AI and Aguilar MI, `b-Amino acids: Versatile peptidomimetics’, Curr. Med. Chem. 9 (2002) 811-822.

Steer D L, Lew R A, Perlmutter, P, Smith A I and Aguilar M I, `Inhibitors of metalloendopeptidase E.C. and EC stabilised against proteolysis by the incorporation of b-amino acids’, Biochemistry, 41 (2002) 10819-10826.

A New, [NARC]-based Enantioselective, Synthesis of Cyclic b-Amino Acids. Perlmutter, P.; Rose, M.; Vounatsos, F. Eur. J. Org. Chem., 4, (2003), 756-760.

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