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Associate Professor Mibel Aguilar
Dept of Biochemistry & Molecular Biology
Monash University
Clayton, Vic 3800
Email: Mibel.Aguilar@med.monash.edu.au
Tel: +61-3-9905-3723
Fax: +61-3-9905-5882

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 Dr Patrick Perlmutter (Department of Chemistry) 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 Dr Perlmutter and Assoc.Prof Smith has developed the use of b-amino acids for the design of enzyme inhibitors with potential cardiovascular applications and has generated a number of publications and one patent. These publications were the first studies to demonstrate that b-amino acids could be used to convert peptide substrates into proteolytically-resistant enzyme inhibitors.
Steer D L, Lew R A, Perlmutter, P, Smith A I and Aguilar M I, `Design and synthesis of inhibitors incorporating b-amino acids of metalloendopeptidase E.C.’, J Pept Sci, 6 (2000) 470-477.

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.

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