Biochemistry and Molecular Biophysics
Publications (PubMed / NIH)
Research
The Janetka research laboratory is broadly interested in the X-ray structure-based drug design, medicinal chemistry and organic synthesis of chemical tools and small molecule drugs. In multiple drug discovery projects, we are developing inhibitors of proteases, kinases, lectins, and other protein targets for studying and treating cancer and a variety of infectious disease. One project is targeting several serine proteases including HGFA and hepsin which activate growth factors and cytokines in tumors. Another project is working on inhibitors of transmembrane serine proteases such as TMPRSS2 and matriptase as broad-spectrum antiviral drugs. We have a project focused on aspartic protease inhibitors and GPCR antagonists as novel therapy for River Blindness, caused by parasitic filarial worm infections. We are also working on phosphodiesterase inhibitors as well as inhibitors of PIM kinase and others as new anthelmintic drugs to treat intestinal worm infections caused by whipworm and hookworm. Further studies are directed on the rational design of CDPK1 kinase inhibitors as novel drugs to treat acute and cure chronic Toxoplasmosis. Finally, a large research effort is dedicated to the structure-guided design of glycomimetic lectin antagonists such as PapG as innovative antivirulence therapeutics for the treatment and prevention of bacterial infections and in one project targeting Fap2 for colon cancer.
Select Patents
Compounds and methods for treating bacterial infections (US Patent # 20180194792)
Inhibitors of growth factor activation enzymes (US Patent # 20180066015)
Select Books
Extracellular Targeting of Cell Signaling in Cancer: Strategies Directed at MET and RON Receptor Tyrosine Kinase Pathways, available from the publisher (Wiley), Amazon, Barnes & Noble, and other bookstores.
Select Publications
Matthew W Mahoney, Jonathan Helander, Anoopjit S Kooner, Mariah Norman, Vishnu C Damalanka, Paolo De Bona, Paulina Kasperkiewicz, Wioletta Rut, Marcin Poreba, Maithri M Kashipathy, Kevin P Battaile, Scott Lovell, Anthony J O’Donoghue, Charles S Craik, Marcin Drag & James W Janetka (2024). “Use of protease substrate specificity screening in the rational design of selective protease inhibitors with unnatural amino acids: Application to HGFA, matriptase, and hepsin” Protein Sci. 2024 Aug;33(8):e5110. doi: 10.1002/pro.5110. (Abstract)
Vishnu C Damalanka, Victoria Banas, Paolo De Bona, Maithri M Kashipathy, Kevin Battaile, Scott Lovell, James W Janetka (2024). “Mechanism-Based Macrocyclic Inhibitors of Serine Proteases” J Med Chem. 2024 Mar 28;67(6):4833-4854. doi: 10.1021/acs.jmedchem.3c02388. Epub 2024 Mar 13. (Abstract)
Robert Obermann, Bereket Yemane, Cassie Jarvis, Francisco M Franco, Yevhenii Kyriukha, William Nolan, Beth Gohara, Andrzej M Krezel, Scott A Wildman & James W Janetka (2024). “Small Molecule Antagonists of the DNA Repair ERCC1/XPA Protein-Protein Interaction” ChemMedChem. 2024 Apr 16;19(8):e202300648. doi: 10.1002/cmdc.202300648. Epub 2024 Mar 5. (Abstract)
Adrianus C M Boon, Traci L Bricker, Ethan J Fritch, Sarah R Leist, Kendra Gully, Ralph S Baric, Rachel L Graham, Brigid V Troan, Matthew Mahoney & James W Janetka (2024). “Efficacy of Host Cell Serine Protease Inhibitor MM3122 against SARS-CoV-2 for Treatment and Prevention of COVID-19” J Virol.2024 May 14;98(5):e0190323. doi: 10.1128/jvi.01903-23. Epub 2024 Apr 9. (Abstract)
Amarendar Reddy Maddirala, Kevin Tamadonfar, Jerome S Pinkner, Denise Sanick, Scott J Hultgren & James W Janetka (2024). “Discovery of Orally Bioavailable FmlH Lectin Antagonists as Treatment for Urinary Tract Infections” J Med Chem. 2024 Mar 14;67(5):3668-3678. doi: 10.1021/acs.jmedchem.3c02128. Epub 2024 Feb 3. (Abstract)
Alpha Raj Mekapogu, Zhihong Xu, Srinivasa Pothula, Chamini Perera, Tony Pang, S M Zahid Hosen, Vishnu Damalanka, James Janetka, David Goldstein, Romano Pirola, Jeremy Wilson & Minoti Apte (2023). “HGF/c-Met pathway inhibition combined with chemotherapy increases cytotoxic T-cell infiltration and inhibits pancreatic tumour growth and metastasis” Cancer Lett. 2023 Aug 1:568:216286. doi: 10.1016/j.canlet.2023.216286. Epub 2023 Jun 22. (Abstract)
Denis Belitškin, Pauliina Munne, Shishir M Pant, Johanna M Anttila, Ilida Suleymanova, Kati Belitškina, Daniel Kirchhofer, James Janetka, Taivo Käsper, Sami Jalil, Jeroen Pouwels, Topi A Tervonen & Juha Klefström (2024). “Hepsin promotes breast tumor growth signaling via the TGFβ-EGFR axis” Mol Oncol. 2024 Mar;18(3):547-561. doi: 10.1002/1878-0261.13545. Epub 2023 Nov 13. (Abstract)
Vivian Truong Jones, Ramona Graves-Deal, Zheng Cao, Galina Bogatcheva, Marisol A Ramirez, Sarah J Harmych, James N Higginbotham, Vineeta Sharma, Vishnu C Damalanka, Claudia C Wahoski, Neeraj Joshi, Maria Johnson Irudayam, Joseph T Roland, Gregory D Ayers, Qi Liu, Robert J Coffey, James W Janetka & Bhuminder Singh (2024). “Inhibition of autocrine HGF maturation overcomes cetuximab resistance in colorectal cancer” Cell Mol Life Sci. 2024 Jan 12;81(1):28. doi: 10.1007/s00018-023-05071-5. (Abstract)
Liana Beld, Hyeim Jung, Christina A. Bulman, Bruce A. Rosa, Peter U. Fischer, James W. Janetka, Sara Lustigman, Judy A. Sakanari, and Makedonka Mitreva (2022). “Aspartyl Protease Inhibitors as Anti-Filarial Drugs” Pathogens. 2022 Jun 18;11(6):707. doi: 10.3390/pathogens11060707. (Abstract)
Vishnu C. Damalanka, Jorine J. L. P. Voss, Matthew W. Mahoney, Tina Primeau, Shunqiang Li, Lidija Klampfer, & James W. Janetka (2021). “Macrocyclic Inhibitors of HGF-Activating Serine Proteases Overcome Resistance to Receptor Tyrosine Kinase Inhibitors and Block Lung Cancer Progression” J Med Chem. 2021 Dec 13. doi: 10.1021/acs.jmedchem.1c01671. Online ahead of print. (Abstract)
Matthew Mahoney, Vishnu C. Damalanka, Michael A. Tartell, Dong Hee Chung, André Luiz Lourenco, Dustin Pwee, Anne E. Mayer Bridwell, Markus Hoffmann, Jorine Voss, Partha Karmakar, Nurit Azouz, Andrea M. Klingler, Paul W. Rothlauf, Cassandra E. Thompson, Melody Lee, Lidija Klampfer, Christina Stallings, Marc E. Rothenberg, Stefan Pöhlmann, Sean P. Whelan, Anthony J. O’Donoghue, Charles S. Craik, & James W. Janetka (2021). “A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 and MERS-CoV viral entry and protect human epithelial lung cells” Proc Natl Acad Sci U S A. 2021 Oct 26;118(43):e2108728118. doi: 10.1073/pnas.2108728118. (Abstract)
Lisa K. McLellan, Michael R. McAllaster, Arthur S. Kim, Ľubomíra Tóthová, Patrick D. Olson, Jerome S. Pinkner, Allyssa L. Daugherty, Teri N. Hreha, James W. Janetka, Daved H. Fremont, Scott J. Hultgren, Herbert W. Virgin, & David A Hunstad (2021). “A host receptor enables type 1 pilus-mediated pathogenesis of Escherichia coli pyelonephritis” PLoS Pathog. 2021 Jan 29;17(1):e1009314. doi: 10.1371/journal.ppat.1009314. eCollection 2021 Jan. (Abstract)
Rahul Tyagi, Christina A. Bulman, Fidelis Cho-Ngwa, Chelsea Fischer, Chris Marcellino, Michelle R. Arkin, James H. McKerrow, Case W. McNamara, Matthew Mahoney, Nancy Tricoche, Shabnam Jawahar, James W. Janetka, Sara Lustigman, Judy Sakanari, & Makedonka Mitreva (2021). “An Integrated Approach to Identify New Anti-Filarial Leads to Treat River Blindness, a Neglected Tropical Disease” Pathogens. 2021 Jan 14;10(1):71. doi: 10.3390/pathogens10010071. (Abstract)
Vishnu C. Damalanka, Amarendar Reddy Maddirala, & James W. Janetka (2020). “Novel approaches to glycomimetic design: Development of small molecular weight lectin antagonists” Expert Opin Drug Discov. 2020 Dec 18. doi: 10.1080/17460441.2021.1857721. Online ahead of print. (Abstract)
James W Janetka, Allen T Hopper, Ziping Yang, Jennifer Barks, Mary Savari Dhason, Qiuling Wang, & L David Sibley (2020). “Optimizing Pyrazolopyrimidine Inhibitors of Calcium Dependent Protein Kinase 1 for Treatment of Acute and Chronic Toxoplasmosis” J Med Chem. 2020 Jun 11;63(11):6144-6163. doi: 10.1021/acs.jmedchem.0c00419. Epub 2020 Jun 1. (Abstract)