William H. Simmons, PhD
- Molecular Pharmacology and Therapeutics
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, the 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 does not 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 itself 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 P2. We purified and characterized this enzyme and developed inhibitors that block the active site so that bradykinin cannot bind and be inactivated. In animals that have been subjected to an experimental heart attack followed by reperfusion, giving an inhibitor intravenously at the time of reperfusion can reduce heart damage by about 60%. Similar protection has been seen in animals with an experimental stroke or acute kidney injury. This protective effect of inhibitors can be prevented by a drug that blocks the action of brady-kinin. This observation indicates that the inhibitors are having their beneficial effect by increasing the amount of bradykinin in the tissue. We have now made new, very potent inhibitors of aminopeptidase P2 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, with an emphasis on stroke. Our goal is to work with a pharmaceutical company to further develop one of these compounds as an approved drug.
- Woodard-Grice,A. V.; Lucisano,A. C.; Byrd,J. B.; Stone,E. R.; Simmons,W. H.; Brown,N. J.Sex-dependent and race-dependent association of XPNPEP2 C-2399A polymorphism with angiotensin-converting enzyme inhibitor-associated angioedema Pharmacogenetics and Genomics 2010 ;20(9):532-536
- Ersahin,C.; Szpaderska,A. M.; Orawski,A. T.; Simmons,W. H.Aminopeptidase P isozyme expression in human tissues and peripheral blood mononuclear cell fractions ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS 2005 ;435(2):303-310
- Molinaro,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.Human recombinant membrane-bound aminopeptidase P: production of a soluble form and characterization using novel, internally quenched fluorescent substrates The Biochemical journal 2005 ;385(Pt 2):389-397
- Graham,S. C.; Maher,M. J.; Simmons,W. H.; Freeman,H. C.; Guss,J. M.Structure of Escherichia coli aminopeptidase P in complex with the inhibitor apstatin Acta crystallographica.Section D, Biological crystallography 2004 ;60(Pt 10):1770-1779
- Ersahin,C.; Szpaderska,A. M.; Simmons,W. H.Rat and mouse membrane aminopeptidase P: structure analysis and tissue distribution ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS 2003 ;417(2):131-140