Dataset Information

Novel Approaches and Challenges of Discovery of Exosite Modulators of a Disintegrin and Metalloprotease 10.

ABSTRACT: A disintegrin and metaproteinase 10 is an important target for multiple therapeutic areas, however, despite drug discovery efforts by both industry and academia no compounds have reached the clinic so far. The lack of enzyme and substrate selectivity of developmental drugs is believed to be a main obstacle to the success. In this review, we will focus on novel approaches and associated challenges in discovery of ADAM10 selective modulators that can overcome shortcomings of previous generations of compounds and be translated into the clinic.

SUBMITTER: Minond D

PROVIDER: S-EPMC7218085 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Novel Approaches and Challenges of Discovery of Exosite Modulators of a Disintegrin and Metalloprotease 10.

Minond Dmitriy D

Frontiers in molecular biosciences 20200506

A disintegrin and metaproteinase 10 is an important target for multiple therapeutic areas, however, despite drug discovery efforts by both industry and academia no compounds have reached the clinic so far. The lack of enzyme and substrate selectivity of developmental drugs is believed to be a main obstacle to the success. In this review, we will focus on novel approaches and associated challenges in discovery of ADAM10 selective modulators that can overcome shortcomings of previous generations o ...[more]

PMID: 32435655

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Project description:A disintegrin and metalloprotease (ADAM) proteases are implicated in multiple diseases, but no drugs based on ADAM inhibition exist. Most of the ADAM inhibitors developed to date feature zinc-binding moieties that target the active site zinc, which leads to a lack of selectivity and off-target toxicity. We hypothesized that secondary binding site (exosite) inhibitors should provide a viable alternative to active site inhibitors. Potential exosites in ADAM structures have been reported, but no studies describing substrate features necessary for exosite interactions exist. Analysis of ADAM cognate substrates revealed that glycosylation is often present in the vicinity of the scissile bond. To study whether glycosylation plays a role in modulating ADAM activity, a tumor necrosis factor ? (TNF?) substrate with and without a glycan moiety attached was synthesized and characterized. Glycosylation enhanced ADAM8 and -17 activities and decreased ADAM10 activity. Metalloprotease (MMP) activity was unaffected by TNF? substrate glycosylation. High throughput screening assays were developed using glycosylated and non-glycosylated substrate, and positional scanning was conducted. A novel chemotype of ADAM17-selective probes was discovered from the TPIMS library (Houghten, R. A., Pinilla, C., Giulianotti, M. A., Appel, J. R., Dooley, C. T., Nefzi, A., Ostresh, J. M., Yu, Y., Maggiora, G. M., Medina-Franco, J. L., Brunner, D., and Schneider, J. (2008) Strategies for the use of mixture-based synthetic combinatorial libraries. Scaffold ranking, direct testing in vivo, and enhanced deconvolution by computational methods. J. Comb. Chem. 10, 3-19; Pinilla, C., Appel, J. R., Borràs, E., and Houghten, R. A. (2003) Advances in the use of synthetic combinatorial chemistry. Mixture-based libraries. Nat. Med. 9, 118-122) that preferentially inhibited glycosylated substrate hydrolysis and spared ADAM10, MMP-8, and MMP-14. Kinetic studies revealed that ADAM17 inhibition occurred via a non-zinc-binding mechanism. Thus, modulation of proteolysis via glycosylation may be used for identifying novel, potentially exosite binding compounds. The newly described ADAM17 inhibitors represent research tools to investigate the role of ADAM17 in the progression of various diseases.

Dataset Information

Novel Approaches and Challenges of Discovery of Exosite Modulators of a Disintegrin and Metalloprotease 10.

Publications

Novel Approaches and Challenges of Discovery of Exosite Modulators of a Disintegrin and Metalloprotease 10.

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