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Gregg B Fields

Gregg B Fields

Florida Atlantic University, USA

Title: Structure-guided design of selective matrix metalloproteinase (MMP) inhibitors and their application in animal models of multiple sclerosis, sepsis, and osteoarthritis

Biography

Biography: Gregg B Fields

Abstract

Analysis of matrix metalloproteinase (MMP) expression profiles in various pathologies correlated their presence in promoting disease progression. Drugs were designed to inhibit MMPs by chelating the active site zinc ion. This approach did not distinguish between the MMP family members and had devastating consequences during clinical trials. Subsequent knockout mouse studies showed that some MMPs were beneficial in regulating tumor growth and metastasis and stimulating indirectly the immune system. The broad-spectrum inhibitor approach was rethought in order to increase specificity, taking into account the non-conserved secondary binding sites (exosites) within MMPs. Structural evaluation of the collagenolytic mechanisms of MMP-1 and MT1-MMP revealed differences in exosites, facilitating the development of triple-helical peptide inhibitors (THPIs). THPIs achieved selectivity within the MMP family, and showed efficacy in in vivo models of multiple sclerosis and sepsis, where MMP-9 and MMP-8, respectively, were targeted. MMP-13 has been identified to be mainly responsible for the cleavage of type II collagen in osteoarthritis, which leads to the destruction of articular cartilage. The development of an allosteric MMP-13 inhibitor began with a lead compound identified as part of a high throughput screening campaign. Subsequent biochemical experiments and X-ray crystallographic structure determination revealed that our hit bound to the S1’ subsite, which is surrounded by a long loop that differs significantly among MMPs. Comparative structural analysis and molecular modeling enabled the design and synthesis of small molecules three orders of magnitude more potent (IC50 = < 5 nM) than the original hit. Further optimization has led to highly potent and selective inhibitors of MMP-13 with favorable PK properties. The recent technological advances that allow us to better understand the function and structure of MMPs are aiding in the development of selective inhibitors.

References:

  1. Cerofolini L, Amar S, Lauer JL, Martelli T, Fragai M, Luchinat C, Fields GB (2016). Bilayer membrane modulation of membrane type 1 matrix metalloproteinase (MT1-MMP) structure and proteolytic activity. Nat. Sci. Rep. 6:29511.
  2. Bhowmick M, Stawikowska R, Tokmina-Roszyk D, Fields GB (2015). Matrix Metalloproteinase Inhibition by Heterotrimeric Triple-Helical Peptide Transition State Analogs. ChemBiochem 16:1084-1092.
  3. Zhao Y, Marcink T, Gari RRS, Marsh BP, King GM, Stawikowska R, Fields GB, Van Doren SR (2015). Transient Collagen Triple Helix Binding to a Key Metalloproteinase in Invasion and Development. Structure 23:257-269.
  4. Spicer TP, Jiang J, Taylor AB, Choi JY, Hart PJ, Roush WR, Fields GB, Hodder PS, Minond D (2014). Characterization of Selective Exosite-Binding Inhibitors of Matrix Metalloproteinase 13 That Prevent Articular Cartilage Degradation In Vitro. J. Med. Chem. 57:9598-9611.
  5. Bertini I, Fragai F, Luchinat C, Melikian M, Toccafondi M, Lauer JL, Fields GB (2012). Structural Basis for Matrix Metalloproteinase 1-Catalyzed Collagenolysis. J. Am. Chem. Soc. 134:2100-2110.