Department of Chemistry
Faculty, Graduate Program
Utilizing principles grounded in bioorganic- biological- and physical organic-chemistry, biochemistry and molecular biology, research in the Wentworth group is highly interdisciplinary, but is directed toward the focused goal of improving our knowledge of major pathological syndromes at the molecular level and thus enabling the development of new diagnostic and/or therapeutic tools to tackle these problems.
Antibody-Catalyzed Water Oxidation Pathway
Recently we have discovered that all immunoglobulins have an intrinsic ability to generate a cascade of reactive oxygen species when presented with singlet (1?g) oxygen. This property is significant for a number of reasons: Antibodies are a diverse library of proteins whose sole function, first described by Prof. Paul Erhlich, was thought to be to link the effector arm of the immune system, phagocytosis and complement activation, to its target antigen. This new chemical potential of the immune system challenges this dogma and hints that under appropriate conditions antibodies can destroy their antigen without the requisite need for effector function activation. We are investigating this pathway to understand its chemical mechanism, the structural location within the antibody structure where it occurs and the biological significance of this ability.
Cholesterol Ozonolysis Products and Atherosclerosis
We have recently uncovered a new class of oxysterols in human atheromatous artery extracts. These molecules are ozonolysis products of LDL-cholesterol and we have termed them the atheronals. While the chemical and/or biochemical origin of these new biologically-relevant sterols is under intensive investigation the most immediate potential impact of these molecules is as new potential biomarkers of atherosclerosis progression. In this regard we have developed LC-MS, IDGC-MS and ELISA procedures for their detection and analysis in multi-species biological samples. These sterols have never before been shown to be present in vivo and therefore we are also investigating the potential impact of the atheronals on all aspects of atherosclerosis.
Inflammatory Aldehydes and Misfolding diseases
Aldehydes in vivo can be derived from a number of sources during indolent inflammatory disease, both chemically and enzymatically. We have recently discovered that certain inflammatory-derived aldehydes, such as the atheronals trigger misfolding of b-amyloid protein when bound covalently via a Schiff-Base to component lysine residues. This aldehyde-initiated misfolding leads to amyloid plaque indistinguishable at the molecular level from the type implicated in Alzheimer's diease neuropathy. The discovery that atherosclerosis-derived aldehydes may be implicated in Alzheimer's disease offers the first chemical link between the two diseases already known to share both epistemological and genetic risk factors. Using a combination of mouse-models, bio-organic and physical organic chemistry techniques, we are investigating the molecular basis and scope of 'covalent' protein modification-initiated protein misfolding in both normally folded and unfolded proteins that have pathological consequences. We are also attempting to perturb such modifications, using traditional medicinal chemistry, as a novel therapeutic strategy for misfolding diseases that have an inflammatory arm.
B.S., Chemistry and Pharmacology, The University of Sheffield, 1991
Ph.D., Organic Chemistry, The University of Sheffield, 1994
Awarded title of Professor of Medicinal Chemistry, during the recognition of distinction excercise, University of Oxford, UK 2004; Member IUPAC Organic and Biomolecular Chemistry Division (III), subcommittee on Biotechnology; Editorial Advisory Board: Current Medicinal Chemistry, Current Organic Chemistry; Consultant: Pharmacyclics Inc.
Nyffeler PT, Boyle NA, Laxman E, Wong C-H, Eschenmoser A, Lerner RA, Wentworth Jr. P. Dihydrogen trioxide (HOOOH) is generated during the thermal reaction between hydrogen peroxide and ozone. Angew. Chem. 2004;in press.
Wentworth Jr. P, Nieva J, Takeuchi C, Galve R, Wentworth AD, Dilley RB, DeLaria GA, Saven A, Babior BM, Janda KD, Eschenmoser A, Lerner RA. Evidence for ozone generation in human atherosclerotic arteries. Science 2003;302:1053-1057.
Wentworth Jr. P, McDunn J, Wentworth AD, Takeuchi C, Nieva J, Janda KD, Eschenmoser A, Lerner RA. Evidence for antibody-catalyzed ozone formation in bacterial killing and inflammation. Science 2002;298:2195-2199.
Wentworth Jr. P, Jones LH, Wentworth AD, Zhu X, Larsen NA, Wilson IA, Xu X, Goddard III WA, Janda KD, Eschenmoser A, Lerner RA. Antibody catalysis of the oxidation of water. Science 2001;293:1806-1809.