Vice President of Scientific Affairs, Florida
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Dr. Fields research interests are in extracellular matrix biochemistry, synthetic protein design and construction, proteases of the extracellular matrix, cancer chemical biology, biomimetic biomaterials for drug delivery, tumor cell biology/signal transduction, and solid-phase peptide synthesis methodology.
The dissolution of the collagen triple-helix has been implicated in diseases where the structural integrity of various components of the body is compromised (for example, arthritis and multiple sclerosis). Collagen also provides a barrier to “compartmentalize” cellular activities; destruction of this barrier plays a role in tumor cell invasion and metastasis. The matrix metalloproteinase (MMP) family has been recognized for their collagenolytic activities, and has thus been the subject of intense research efforts, in order to elucidate their mechanisms of action and allow for rational design of inhibitors. Our laboratory has created and utilized a “mini-library” of collagen-model triple-helical substrates to gain significant insight into the mechanism of collagenolysis, as well as identifying secondary binding sites (exosites) that contribute to collagenolysis.
The work on triple-helical peptidase activity has led our laboratory to consider unique approaches for designing inhibitors targeted for collagenolytic proteases. Rather than focus on small molecules, we have utilized a mini-protein approach to develop agents that interact with multiple sites within the protease, increasing selectivity. The first generation of these inhibitors, triple-helical transition state analogs, have provided high affinity and unique selectivities not observed previously in the MMP field.
Our laboratory has utilized mini-protein approaches to create structurally accurate models of collagen to (a) identify specific regions within collagen that were bound by metastatic melanoma cells, (b) identify the melanoma cell receptors that bound to these regions, (c) evaluate the results of outside-in signal transduction mediated by those receptors, (d) correlate the three-dimensional structural state of collagen with promotion of melanoma activities, and (e) “proteolytically profile” metastatic potential. As a result, triple-helical ligands for the α2β1 and α3β1 integrins and CD44/chondroitin sulfate proteoglycan (CSPG) were developed. These ligands were used in a novel approach for creating targeted nanoDDSs, involving the direct incorporation of peptide amphiphiles (PAs) into liposomal vesicles. Stable PA nanoDDSs allowed for selective delivery to CD44-positive melanoma cells. Overall, the progression of melanoma was found to be partially dictated by the structural state of collagen.
In the course of the studies described above, glycosylation was found to strongly modulate melanoma cell activities, as adhesion and spreading were dramatically decreased due to the presence of glycosylated hydroxylysine residues within the collagen triple-helix. Overall, this (a) was the first demonstration of the prophylactic effects of glycosylation on tumor cell interaction with the basement membrane, (b) provided a rare example of an apparent unfavorable interaction between carbohydrates, and (c) suggested that sugars may mask “cryptic sites” accessible to tumor cells containing cell-surface or secreted glycosidase activities.
Dr. Gregg B. Fields received his B.S. and Ph.D. degrees in chemistry from the University of Florida and Florida State University, respectively. He was a Postdoctoral Scholar with Ken A. Dill at the University of California San Francisco. Dr. Fields joined the faculty at the University of Minnesota in 1991 as an assistant professor. He was promoted to associate professor with tenure in 1995 and then achieved the rank of full professor of chemistry & biochemistry at Florida Atlantic University in 1997. In 2008, Dr. Fields became a Robert A. Welch Foundation Distinguished University Chair in Chemistry in the Department of Biochemistry at The University of Texas Health Science Center at San Antonio. Dr. Fields recently relocated to the Torrey Pines Institute for Molecular Studies, where he is a Full Member, Director of Research, and Distinguished Chair of Metalloproteinase and Multiple Sclerosis Research. Dr. Fields' research interests are in the use of chemical approaches to better understand how protein three-dimensional structures influence cellular and enzymatic behaviors. Early studies by Dr. Fields included the systematic examination of mild methodologies for solid-phase synthesis of small proteins. Chemical approaches were used to develop “mini-protein” models for the study of cellular recognition processes, which in turn allowed for the mapping of protein domains involved in tumor cell binding and signal transduction. Mini-protein models have subsequently been utilized to dissect the mechanisms of collagen catabolism, and in the process have provided new avenues for protease inhibitor design. Dr. Fields has authored or coauthored more than 200 scientific publications and presented over 100 invited lectures. Dr. Fields is currently President of the American Peptide Society (2009-2011).