title: Enhanced potency of the metalloprotease inhibitor TAPI-2 by multivalent display.
abstract: Metalloproteases regulate a vast array of critical cellular processes such as proliferation, migration, repair, and invasion/metastasis. In so doing, metalloproteases have been shown to play key roles in the pathogenesis of multiple disorders including arteriosclerosis, arthritis, cancer metastasis, and ischemic brain injury. Therefore, much work has focused on developing metalloprotease inhibitors to provide a potential therapeutic benefit against the progression of these and other diseases. In order to produce a more potent inhibitor of metalloproteases, we synthesized multivalent displays of a metalloprotease inhibitor derived from the ring-opening metathesis polymerization (ROMP). Specifically, multivalent ligands of a broad-spectrum metalloprotease inhibitor, TAPI-2, were generated upon conjugation of the amine-bearing inhibitor with the ROMP-derived N-hydroxysuccinimide ester polymer. By monitoring the metalloprotease dependent cleavage of the transmembrane protein Semaphorin4D (Sema4D), we demonstrated an enhancement of inhibition by multivalent TAPI-2 compared to monovalent TAPI-2. To further optimize the potency of the multivalent inhibitor, we systematically varied the polymer length and inhibitor ligand density (mole fraction, χ). We observed that while ligand density plays a modest role in the potency of inhibition caused by the multivalent TAPI-2 display, the length of the polymer produces a much greater effect on inhibitor potency, with the shortest polymer achieving the greatest level of inhibition. These findings validate the use of multivalent display to enhance the potency of metalloprotease inhibitors and further, suggest this may be a useful approach to enhance potency of other small molecule towards their targets.
authors.affiliation: Department of Biology, National Center for Behavioral Genomics, and Volen Center for Complex Systems, Brandeis University, Waltham, MA 02454, United States.
authors.forename: Aram J
authors.initials: AJ
authors.lastname: Raissi
authors.affiliation: Department of Biology, National Center for Behavioral Genomics, and Volen Center for Complex Systems, Brandeis University, Waltham, MA 02454, United States; Department of Chemistry, Brandeis University, Waltham, MA 02454, United States.
authors.forename: Frank A
authors.initials: FA
authors.lastname: Scangarello
authors.affiliation: Department of Chemistry, Brandeis University, Waltham, MA 02454, United States.
authors.forename: Kaitlin R
authors.initials: KR
authors.lastname: Hulce
authors.affiliation: Department of Chemistry, Brandeis University, Waltham, MA 02454, United States. Electronic address: pontrell@brandeis.edu.
authors.forename: Jason K
authors.initials: JK
authors.lastname: Pontrello
authors.affiliation: Department of Biology, National Center for Behavioral Genomics, and Volen Center for Complex Systems, Brandeis University, Waltham, MA 02454, United States. Electronic address: paradis@brandeis.edu.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Paradis
mesh_terms: D015153:Blotting, Western; D004789:Enzyme Activation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry* / Q000494:pharmacology*; D045726:Metalloproteases / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D039961:Semaphorins / Q000378:metabolism
chemical_list: D006877:Hydroxamic Acids; D011480:Protease Inhibitors; D039961:Semaphorins; C099410:TAPI-2; D045726:Metalloproteases
keywords: Cleavage; Metalloprotease; Multivalent; Semaphorin4D; TAPI-2