Micky D Tortorella
Guangzhou Institutes of Biomedicine and Health
Chinese Academy of Sciences
Room A419
190 Kai Yuan Avenue, Science Park
Guangzhou, China 510530
(Cell China) 186-8888-8347
(Email China)
(Cell USA) 636-293-9612
(Email USA)
Background:
The extracellular matrix (ECM) comprises a complex network of many macromolecules such as proteoglycans, collagens, glycoproteins and polysaccharides. These matrix proteins play an essential role in the assembly of cells to form tissues and provide the correct environment for cell migration, differentiation and growth. ECM remodeling is important in numerous biological processes including tissue resorption and repair. My previous work has focused on understanding the biochemical mechanisms involved in the turnover and degradation of the cartilage ECM, which led to the discovery, characterization and crystallization of ADAMTS-4 and -5, two enzymes responsible for aggrecan catabolism in arthritic diseases. Some of my current research continues to focus on elucidating the mechanisms that mediate cartilage and bone degradation during the progression of osteoarthritis (OA) and developing therapies for blocking these processes using innovative biochemical, biophysical, molecular and cell imaging technologies.
The illustration depicts an overlay of the crystal structure of the catalytic domain of ADAMTS-5, a protease responsible for the breakdown of the matrix molecule aggrecan, bound to an inhibitor and eroding human, osteoarthritic articular cartilage stained with hematoxylin and eosin.
Interests:
(1) To lead and provide direction to a discovery team and apply basic biology to the drug discovery process, including identification of novel targets, innovation in assay development and in vivo models of disease. (2) The role of proteinases in mediating the breakdown of the extracellular matrix in disease.
Experience:
2009 – Present Guangzhou Institutes of Biomedicine and Health (GIBH), Guangzhou China
Chief Technology Officer & Vice President of Drug Discovery Research
· Establish the overall strategic direction for the Drug Discovery Pipeline (DDP) at GIBH.
· Provide leadership to enable the discovery of new targets and the development of innovative small molecule therapeutics in response to unmet medical needs within multiple therapeutic areas.
· Insure that a sufficient number of new chemical entities are successfully promoted to the Development Track each year, enhancing the pipeline of drugs necessary for GIBH’s sustainable growth.
· Oversee the DDP, which includes: Medicinal Chemistry, Structural Biology, Screening, PK/PD and Biomarkers.
· Coordinated the successful creation of several companies in China using assets developed at GIBH including GZstem (stem cell based company) in 2010.
2003 — 2009 Pfizer, St Louis Missouri
Senior Principal Scientist (Inflammatory Diseases)
· Project leader (OA target).
· Project champion (2 OA targets).
· Coordinated the efforts of multiple team members to establish objectives, strategies and timelines.
· Studied the role of proprotein convertases in the activation of latent metalloproteinases in articular cartilage.
· Developed peptide therapeutics for intra-articular injection for the treatment of OA.
· Studied the dynamic relationship between aggrecan and collagen breakdown, chondrocyte cloning, chondrocyte apoptosis, osteophyte formation, subchondral bone sclerosis and pain using KO mice.
· Established external strategic alliances to advance project goals.
2001 — 2003 Pharmacia*, Skokie, Illinois. *Acquired by Pfizer in 2003
Senior Principal Scientist (Joint Biology)
· Project leader (OA target).
· Coordinated the efforts of multiple team members to establish objectives, strategies and timelines.
· Studied the role of ADAMTS proteins in arthritic diseases.
· Identified several novel mediators of cartilage degradation in osteoarthritis using pathway mapping and proteonomics.
· Validated multiple biomarkers of cartilage degradation.
1999 — 2001 Imperial College of London, Kennedy Institute of Rheumatology, Hammersmith, London.
Research Scientist (Matrix Biology)
· Studied the role of cartilage aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5) in in vitro and in vivo models of cartilage degradation.
· Explored the role of fibronectin peptides in mediating cartilage erosion and the mRNA and protein expression of aggrecanases.
· Researched the role of a novel activity “fibronectinases” in the cleavage of cartilage fibronectin and its importance in cartilage metabolism
· Examined the role of an enzyme involved in the C-terminal truncation of aggrecan in older adults and the potential link to OA.
· Designed multiple-site-binding inhibitors (substrate plus enzyme).
DuPont Pharmaceuticals, Wilmington, Delaware.
1997 — 1999 Research Scientist
1994 — 1997 Staff Scientist
1992 — 1994 Associate Scientist
· Studied the role of MMPs in the breakdown of articular cartilage.
· Identified and purified two novel metalloproteinases, aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5) in bovine nasal cartilage implicated in the breakdown of aggrecan in OA.
· Characterized the enzyme activity and substrate specificity of ADAMTS-4 and ADAMTS-5.
· Developed and validated several aggrecan neoepitope antibodies as biomarkers of cartilage breakdown.
Education:
1999 — 2001 Imperial College of London, Kennedy Institute of Rheumatology, Hammersmith, London. Graduate student in the biochemistry department.
1985 — 1990 University of Delaware, Newark, Delaware.
Bachelors in Biological Sciences (Biochemistry track), Cum Laude, GPA 3.5/4.0 Class rank 232/2918; Dean’s list 7/9 semesters.
Laboratory Proficiencies:
- PCR - Enzyme assays - Protein expression
- Cloning - Tissue culture - Mass spectrometry
- Peptide chemistry - Cell labelling - Molecular modelling
- Affinity sensor - Protein purification - ELISA
- Western/Northern - HTS screening - Protein binding assays
- N-terminal sequencing - HPLC - Enzymology
Patents:
o USP 20050090466: Inhibitors of PACE4 for the treatment of arthritis.
o USP 6753176: Aggrecan degrading metallo proteases.
o USP 6521436: Nucleic acids encoding aggrecan degrading metallo
proteases.
o USP 6451575: Aggrecan degrading metallo proteases.
o USP 6326162: Assays and peptide substrate for determining aggrecan
degrading metallo protease activity.
o USP Application 60/145527: Thrombospondin Peptides that Inhibit Aggrecanase Activity.
o WO 03/005956: A Hydroxamic Acid Thrombospondin Peptide Analog that Inhibits Aggrecanase Activity.
o USP 6635430: Filtrate plate device and reversible-well plate device.
o USP 2005037432A: Novel biomarkers of aggrecanase activity.
External Collaborations & Strategic Alliances
· Professor Anne-Marie Malfait, PhD, MD at Rush Medical Center (www.rush.edu). Understanding the biochemistry of OA pain using transgenic mice.
· The Center for World Health & Medicine at Saint Louis University (www.cwhm.org). Development of inhibitors of plasmepsin V as novel anti-malarial agents.
· John J. Talley, PhD and Mark Obukowicz, PhD. Development of 3rd generation Cox-2 selective inhibitors for the treatment of inflammation-mediated cancers.
· Professor Jufang He, PhD at Hong Kong Polytechnic University (http://www.polyu.edu.hk). Advancement of CCKBR agonists for the improvement of memory.
· Dr. Jinsong Zhu, CEO of Plexera Inc. (www.plexera.com). Development of compound micro-array chips for rapid repositioning of clinical candidate compounds.
Publications:
1. Yanmei Zhang, Wei-Xing Dan, Jianqi Liu, Micky D. Tortorella, Zhengchao Tu and John J Talley
Palladium-catalyzed synthesis of trimethylsilyl substituted benzopyran derivatives
(2013) The Open Organic Chemistry Journal 7, pp.15-20.
2. Miller RE, Lu Y, Tortorella MD, Malfait AM.
Genetically engineered mouse models reveal the importance of proteases as osteoarthritis drug targets
(2013) Curr Rheumatol Rep.15(8):350.
3. Morgen, M., Tung, D., Boras, B., Miller, W., Malfait, A.-M., Tortorella, M.
Nanoparticles for improved local retention after intra-articular injection into the knee joint
(2013)Pharmaceutical Research,30(1),pp.257-268.Cited 1 time.
4. Malfait, A.-M., Seymour, A.B., Gao, F., Tortorella, M.D., Le Graverand-Gastineau, M.-P.H., Wood, L.S., Doherty, M., Doherty, S., Zhang, W., Arden, N.K., Vaughn, F.L., Leaverton, P.E., Spector, T.D., Hart, D.J., Maciewicz, R.A., Muir, K.R., Das, R., Sorge, R.E., Sotocinal, S.G., Schorscher-Petcu, A., Valdes, A.M., Mogil, J.S.
A role for PACE4 in osteoarthritis pain: Evidence from human genetic association and null mutant phenotype
(2012)Annals of the Rheumatic Diseases,71(6),pp.1042-1048.Cited 4 times.
5. Li, J., Anemaet, W., Diaz, M.A., Buchanan, S., Tortorella, M., Malfait, A.M., Mikecz, K., Sandy, J.D., Plaas, A.
Knockout of ADAMTS5 does not eliminate cartilage aggrecanase activity but abrogates joint fibrosis and promotes cartilage aggrecan deposition in murine osteoarthritis models
(2011)Journal of Orthopaedic Research,29(4),pp.516-522.Cited 14 times.
6. Zhang, S., Chen, S., Li, W., Guo, X., Zhao, P., Xu, J., Chen, Y., Pan, Q., Liu, X., Zychlinski, D., Lu, H., Tortorella, M.D., Schambach, A., Wang, Y., Pei, D., Esteban, M.A.
Rescue of ATP7B function in hepatocyte-like cells from Wilson's disease induced pluripotent stem cells using gene therapy or the chaperone drug curcumin
(2011)Human Molecular Genetics,20(16),art. no.ddr223,pp.3176-3187.Cited 19 times.
7. Shieh, H.-S., Tomasselli, A.G., Mathis, K.J., Schnute, M.E., Woodard, S.S., Caspers, N., Williams, J.M., Kiefer, J.R., Munie, G., Wittwer, A., Malfait, A.-M., Tortorella, M.D.
Structure analysis reveals the flexibility of the ADAMTS-5 active site
(2011)Protein Science,20(4),pp.735-744.Cited 4 times.
6. Dufield, D.R., Nemirovskiy, O.V., Jennings, M.G., Tortorella, M.D., Malfait, A.M., Mathews, W.R.
An immunoaffinity liquid chromatography-tandem mass spectrometry assay for detection of endogenous aggrecan fragments in biological fluids: Use as a biomarker for aggrecanase activity and cartilage degradation
(2010)Analytical Biochemistry,406(2),pp.113-123.Cited 12 times.
7. Byun, S., Tortorella, M.D., Malfait, A.-M., Fok, K., Frank, E.H., Grodzinsky, A.J.
Transport and equilibrium uptake of a peptide inhibitor of PACE4 into articular cartilage is dominated by electrostatic interactions
(2010)Archives of Biochemistry and Biophysics,499(1-2),pp.32-39.Cited 5 times.
8. Malfait, A.M., Ritchie, J., Gil, A.S., Austin, J.-S., Hartke, J., Qin, W., Tortorella, M.D., Mogil, J.S.
ADAMTS-5 deficient mice do not develop mechanical allodynia associated with osteoarthritis following medial meniscal destabilization
(2010)Osteoarthritis and Cartilage,18(4),pp.572-580.Cited 19 times.
9. Zack, M.D., Melton, M.A., Stock, J.L., Storer, C.E., Barve, R.A., Minnerly, J.C., Weiss, D.J., Stejskal, J.A., Tortorella, M.D., Turk, J.R., Shevlin, K.M., Malfait, A.-M.
Reduced incidence and severity of experimental autoimmune arthritis in mice expressing catalytically inactive A disintegrin and metalloproteinase 8 (ADAM8)
(2009)Clinical and Experimental Immunology,158(2),pp.246-256.Cited 7 times.
10. Tortorella, M.D., Tomasselli, A.G., Mathis, K.J., Schnute, M.E., Woodard, S.S., Munie, G., Williams, J.M., Caspers, N., Wittwer, A.J., Malfait, A.-M., Shieh, H.-S.
Structural and inhibition analysis reveals the mechanism of selectivity of a series of aggrecanase inhibitors
(2009)Journal of Biological Chemistry,284(36),pp.24185-24191.Cited 20 times.
11. Zack, M.D., Malfait, A.-M., Skepner, A.P., Yates, M.P., Griggs, D.W., Hall, T., Hills, R.L., Alston, J.T., Nemirovskiy, O.V., Radabaugh, M.R., Leone, J.W., Arner, E.C., Tortorella, M.D.
ADAM-8 isolated from human osteoarthritic chondrocytes cleaves fibronectin at Ala271
(2009)Arthritis and Rheumatism,60(9),pp.2704-2713.Cited 8 times.
12. Tortorella, M.D., Malfait, F., Barve, R.A., Shieh, H.-S., Malfait, A.-M.
A review of the ADAMTS family, pharmaceutical targets of the future
(2009)Current Pharmaceutical Design,15(20),pp.2359-2374.Cited 18 times.
13. Malfait, A.M., Tortorella, M., Thompson, J., Hills, R., Meyer, D.M., Jaffee, B.D., Chinn, K., Ghoreishi-Haack, N., Markosyan, S., Arner, E.C.
Intra-articular injection of tumor necrosis factor-α in the rat: an acute and reversible in vivo model of cartilage proteoglycan degradation
(2009)Osteoarthritis and Cartilage,17(5),pp.627-635.Cited 5 times.
14. Malfait, A.-M., Arner, E.C., Song, R.-H., Alston, J.T., Markosyan, S., Staten, N., Yang, Z., Griggs, D.W., Tortorella, M.D.
Proprotein convertase activation of aggrecanases in cartilage in situ
(2008)Archives of Biochemistry and Biophysics,478(1),pp.43-51.Cited 30 times.
15. Tortorella, M.D., Malfait, A.M.
Will the real aggrecanase(s) step up: Evaluating the criteria that define aggrecanase activity in osteoarthritis
(2008)Current Pharmaceutical Biotechnology,9(1),pp.16-23.Cited 18 times.
16. Shieh, H.-S., Mathis, K.J., Williams, J.M., Hills, R.L., Wiese, J.F., Benson, T.E., Kiefer, J.R., Marino, M.H., Carroll, J.N., Leone, J.W., Malfait, A.-M., Arner, E.C., Tortorella, M.D., Tomasselli, A.
High resolution crystal structure of the catalytic domain of ADAMTS-5 (aggrecanase-2)
(2008)Journal of Biological Chemistry,283(3),pp.1501-1507.Cited 33 times.
17. Blair, W.S., Cao, J., Jackson, L., Jimenez, J., Peng, Q., Wu, H., Isaacson, J., Butler, S.L., Chu, A., Graham, J., Malfait, A.-M., Tortorella, M., Patick, A.K.
Identification and characterization of UK-201844, a novel inhibitor that interferes with human immunodeficiency virus type 1 gp160 processing
(2007)Antimicrobial Agents and Chemotherapy,51(10),pp.3554-3561.Cited 9 times.
18. Wittwer, A.J., Hills, R.L., Keith, R.H., Munie, G.E., Arner, E.C., Anglin, C.P., Malfait, A.-M., Tortorella, M.D.
Substrate-dependent inhibition kinetics of an active site-directed inhibitor of ADAMTS-4 (aggrecanase 1)
(2007)Biochemistry,46(21),pp.6393-6401.Cited 16 times.
19. Hall, T., Fok, K.F., Liu, M.M., Zobel, J.F., Marino, M.H., Malfait, A.-M., Tortorella, M.D., Tomasselli, A.G.
A high performance liquid chromatography assay for monitoring proprotein convertase activity
(2007)Journal of Chromatography A,1148(1),pp.46-54.Cited 3 times.
20. Hills, R., Mazzarella, R., Fok, K., Liu, M., Nemirovskiy, O., Leone, J., Zack, M.D., Arner, E.C., Viswanathan, M., Abujoub, A., Muruganandam, A., Sexton, D.J., Bassill, G.J., Sato, A.K., Malfait, A.-M., Tortorella, M.D.
Identification of an ADAMTS-4 cleavage motif using phage display leads to the development of fluorogenic peptide substrates and reveals matrilin-3 as a novel substrate
(2007)Journal of Biological Chemistry,282(15),pp.11101-11109.Cited 19 times.
21. Song, R.-H., Tortorella, M.D., Malfait, A.-M., Alston, J.T., Yang, Z., Arner, E.C., Griggs, D.W.
Aggrecan degradation in human articular cartilage explants is mediated by both ADAMTS-4 and ADAMTS-5
(2007)Arthritis and Rheumatism,56(2),pp.575-585.Cited 114 times.
22. Zack, M.D., Arner, E.C., Anglin, C.P., Alston, J.T., Malfait, A.-M., Tortorella, M.D.
Identification of fibronectin neoepitopes present in human osteoarthritic cartilage
(2006)Arthritis and Rheumatism,54(9),pp.2912-2922.Cited 14 times.
23. Tortorella, M.D., Arner, E.C., Hills, R., Gormley, J., Fok, K., Pegg, L., Munie, G., Malfait, A.-M.
ADAMTS-4 (aggrecanase-1): N-Terminal activation mechanisms
(2005)Archives of Biochemistry and Biophysics,444(1),pp.34-44.Cited 43 times.
24. Tortorella, M.D., Arner, E.C., Hills, R., Easton, A., Korte-Sarfaty, J., Fok, K., Wittwer, A.J., Liu, R.-Q., Malfait, A.-M.
α2-Macroglobulin Is a Novel Substrate for ADAMTS-4 and ADAMTS-5 and Represents an Endogenous Inhibitor of These Enzymes
(2004)Journal of Biological Chemistry,279(17),pp.17554-17561.Cited 52 times.
25. Wang, P., Tortorella, M., England, K., Malfait, A.-M., Thomas, G., Arner, E.C., Pei, D.
Proprotein Convertase Furin Interacts with and Cleaves Pro-ADAMTS4 (Aggrecanase-1) in the trans-Golgi Network
(2004)Journal of Biological Chemistry,279(15),pp.15434-15440.Cited 67 times.
26. Tortorella, M.D., Malfait, A.-M.
The Usual Suspects: Verdict Not Guilty?
(2003)Arthritis and Rheumatism,48(12),pp.3304-3307.Cited 10 times.
27. Pratta, M.A., Yao, W., Decicco, C., Tortorella, M.D., Liu, R.-Q., Copeland, R.A., Magolda, R., Newton, R.C., Trzaskos, J.M., Arner, E.C.
Aggrecan Protects Cartilage Collagen from Proteolytic Cleavage
(2003)Journal of Biological Chemistry,278(46),pp.45539-45545.Cited 105 times.