Enzymes have historically been considered attractive drug targets for therapeutics because of their specificity and susceptibility to drug modulation. More than 250 genes coding for enzymes, have been identified as FDA-approved drug targets and this further highlights the continued importance of investigating enzyme targets. Therefore, with the rise in demand for effective therapeutic agents, the development of new processes to manufacture high value-added and bulk drugs using enzymes as biocatalysts is gaining more focus. Advancements in the recombinant DNA technology have significantly aided the increased production of enzymes from microorganisms. Through transfer of the desired enzyme genes from one microbe to another, commonly from the ones with low level synthesis to ones with commercially-viable levels, the desired commercial enzyme can be produced in large volumes.
Enzymes have been identified as disease drivers across various disease states, including cancer, neurological disease, autoimmune diseases, cardiovascular disease, and metabolic disorders. Enzyme replacement therapies are currently used in metabolic diseases where the deficiency of a specific enzyme is the primary cause. Protein kinases, ubiquitin’s, epigenetic enzymes and protease Inhibitors are among the enzymes that are increasingly used in drug discovery.
Ubiquitin modification of proteins plays a pivotal role in the cellular response to DNA damage and the ubiquitin-proteasome system (UPS) plays an important role in cardiac health, including its roles in the pathologic hypertrophy associated with heart failure and its reversal during mechanical unloading. Also, E3 ubiquitin ligases sense major molecular events, which are crucial for human brain development from early embryonic stages and throughout adolescence. A better understanding of these E3 ubiquitin ligases and their interactions with other proteins will provide invaluable insight into disease mechanisms and possible therapeutic interventions. Research has suggested that USP22, a member of the deubiquitinases (DUBs) family is a new therapeutic target for improving the efficacy of chemotherapy in hepatocellular carcinoma patients.
Kinases have been shown to be good therapeutic targets due to their involvement in many cellular functions including proliferation and survival. Epigenetic control of gene transcription is achieved through enzyme-mediated covalent modifications of promoter-region DNA sites and of histone proteins around which chromosomal DNA is wound. Different classes of epigenetic enzymes have been demonstrated to have strong disease association and are currently being targeted for small molecule inhibition. Recent research suggests that tryptase catalyzed histone clipping is a novel epigenetic regulatory mechanism, which in the mast cell context may be crucial for maintaining cellular identity.
Protease inhibitors play crucial roles in impeding parasite development and survival, thereby counteracting the potentially damaging immune responses of their vertebrate hosts. Latest studies on protease inhibitors have revealed that Eppin, a serine protease inhibitor, expressed in male reproductive tissues, may have a role in the innate immune response in the lung; Serine Protease Inhibitor Kazal-Type 6 inhibits tumorigenesis of human hepatocellular carcinoma cells via its extracellular action. PAI-1 (plasminogen activator inhibitor-1) is a member of the evolutionarily conserved serine protease inhibitor family and is a potent and rapid-acting inhibitor of mammalian plasminogen activators. In addition, PAI-1 is not only a marker but also a key mediator of cellular senescence and organismal aging.
The GTCbio 13th Enzymes in Drug Discovery Summit will be held on February 22-23, 2018 in San Diego, CA and the speakers for the key note session include the following:
Judith Clements, Distinguished Professor, Queensland University of Technology
Dr. Clements leads the Cancer Program at the Institute of Health and Biomedical Innovation, QUT, based at the Translational Research Institute on the Princess Alexandra Hospital Biomedical Precinct. Her areas of expertise include prostate and ovarian cancer, with respect to the Kallikrein proteases and their utility as biomarkers and therapeutic targets for cancer progression. She has over 190 publications in scientific journals and collaborates widely with colleagues in the US, Canada, the UK and Europe.
Matthew Bogyo, Professor, Department of Pathology, Stanford University
Dr. Bogyo’s interests are focused on the use of chemistry to study the role of proteases in human disease. In particular, his laboratory is currently working on understanding the role of cysteine proteases in tumorigenesis and in the life cycle of the human parasites, Plasmodium falciparum and Toxoplasma gondii. Dr. Bogyo is a consultant for several biotechnology and pharmaceutical companies in the Bay Area.
Jack Taunton, Professor, Cellular and Molecular Pharmacology, Pharmaceutical Chemistry, University of California, San Francisco
Dr. Taunton is a trained chemist who independently studied cell biology to explore the complex work of cellular proteins. His research focuses on the design and discovery of chemical tools to selectively modulate proteins in living cells, with the aim of inventing small molecules that demystify complex cellular processes relevant to human disease. He is also interested in the mechanisms by which signaling proteins assemble on membrane surfaces to control cytoskeletal and membrane dynamics.