CONTACT INFORMATION http://www.loyola.org
William H. Simmons
Ph.D.
  • Professor
  • Molecular Pharmacology and Therapeutics
Research Keywords
  • Cardiovascular System
  • Hormones
  • Peptides
  • Pharmacotherapy
Research Summary

During a heart attack or ischemic stroke, a blood clot in a vessel blocks the flow of blood to a portion of the heart or brain. If left untreated, the lack of oxygen and nutrients (called ischemia) causes the tissue to die. Current treatments involve either mechanically removing the clot or dissolving it with a clot-busting drug to restore the flow of blood (called reperfusion). Paradoxically, this rapid restoration of blood flow can cause significant tissue damage itself, referred to as “reperfusion injury.” Therefore, opening up a blocked vessel does not have as dramatic of a protective effect on the heart or brain as one would hope. Our lab is interested in preventing this reperfusion injury. Our focus is on the hormone bradykinin, which is produced by blood vessels during ischemia and reperfusion. Bradykinin has the potential to reduce reperfusion injury. However, this hormone doesn’t have a chance to protect the tissue since it is so rapidly inactivated by enzymes on the wall of the blood vessel. Furthermore, it is not practical to administer bradykinin as a drug since blood pressure would decrease to dangerous levels. Our approach is to inhibit a bradykinin-degrading enzyme so that this hormone increases only at the site where it is being produced, i.e., the ischemic vessel. The enzyme that we have studied is called aminopeptidase P. We have purified and characterized this enzyme and developed an inhibitor called apstatin. In animals that have been subjected to an experimental heart attack followed by reperfusion, giving apstatin just before reperfusion can reduce heart damage by about 60%. Similar protection has been seen in animals with an experimental stroke. This protective effect of apstatin can be prevented by a drug that blocks the action of bradykinin. This observation indicates that apstatin is having its beneficial effect by increasing the amount of bradykinin in the tissue. We have now made new, very potent inhibitors of aminopeptidase P that can be effective at very low doses. These chemical compounds have been patented in the U.S. and in several foreign countries. Our lab is currently working to determine if these inhibitors could be useful in other clinical situations that involve ischemia and reperfusion. We are attempting to engage a pharmaceutical company to further develop one of these compounds as an approved drug.

Publications

Sex-dependent and race-dependent association of XPNPEP2 C-2399A polymorphism with angiotensin-converting enzyme inhibitor-associated angioedemaWoodard-Grice,A. V.; Lucisano,A. C.; Byrd,J. B.; Stone,E. R.; Simmons,W. H.; Brown,N. J.Pharmacogenetics and Genomics 2010 ;20(9):532-536

Human recombinant membrane-bound aminopeptidase P: production of a soluble form and characterization using novel, internally quenched fluorescent substratesMolinaro,G.; Carmona,A. K.; Juliano,M. A.; Juliano,L.; Malitskaya,E.; Yessine,M. A.; Chagnon,M.; Lepage,Y.; Simmons,W. H.; Boileau,G.; Adam,A.The Biochemical journal 2005 ;385(Pt 2):389-397

Aminopeptidase P isozyme expression in human tissues and peripheral blood mononuclear cell fractionsErsahin,C.; Szpaderska,A. M.; Orawski,A. T.; Simmons,W. H.ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS 2005 ;435(2):303-310

Structure of Escherichia coli aminopeptidase P in complex with the inhibitor apstatinGraham,S. C.; Maher,M. J.; Simmons,W. H.; Freeman,H. C.; Guss,J. M.Acta crystallographica.Section D, Biological crystallography 2004 ;60(Pt 10):1770-1779

Rat and mouse membrane aminopeptidase P: structure analysis and tissue distributionErsahin,C.; Szpaderska,A. M.; Simmons,W. H.ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS 2003 ;417(2):131-140