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Katherine Seley-Radtke

Contact Information
Office: CHEM 405C
Phone: 410-455-8684

Professor

Post-Doctoral Auburn University 1996; Ph.D. Auburn University 1996; B.A. University of South Florida 1992

Professional Interests

Current Fields of Interest:

Medicinal/Synthetic Bioorganic/Organic Chemistry and Drug Design: Discovery, design and synthesis of nucleoside/nucleotide and heterocyclic enzyme inhibitors with chemotherapeutic emphasis in the areas of antiviral, anticancer, antibiotic, and antiparasitic targets. Primary goals include development of potent inhibitors to shut down disease replication pathways through a combination of cross-disciplinary synthetic, biological screening, mechanistic, and structure-based drug design techniques.

The primary focus for the Seley-Radtke laboratories involves the design and synthesis of flexible nucleoside (“fleximers”) and nucleobases (“flex-bases) inhibitors as a powerful approach to overcome the development of resistance to currently used therapeutics. The fleximers and flex-bases are able retain full potency when faced with “escape mutations” in biologically critical enzymatic systems – the inherent flexibility of the inhibitors allows them to conformationally adjust to steric and electronic clashes encountered in the binding site, and to engage secondary amino acids not previously involved in the enzyme’s mechanism of action. Potent activity has been uncovered with a series of “doubly flexible” acyclic nucleosides and their corresponding prodrugs against various viruses including coronaviruses such as SARS and MERS-CoV. This is particularly notable since to date, no cure has been approved and prior to our discovery, no nucleoside had successfully inhibited coronaviruses. Other targets under investigation with these structurally unique analogues include Ebola and Marburg by inhibition of viral polymerases with fleximers and their corresponding prodrugs. The prodrugs allow the nucleosides to bypass the first rate-limiting kinase-mediated phosphorylation in the requisite intercellular conversion to their biologically active triphosphate form. Other viral targets currently under investigation for the fleximers include Zika, Dengue and Yellow Fever, among other high priority neglected diseases.

Related to the above projects, the use of flex-nucleobases to inhibit the protein-protein interactions (PPIs) for the HIV nucleocapsid NCp7 is also being pursued. NCp7 is of high interest due to its multifunctional role in HIV replication. We have published extensively on a series of non-nucleoside HIV inhibitors (NNRTIs) containing nucleobases that have also shown dual activity against tuberculosis and influenza.

In addition to viral targets, another project focuses on the use of nucleobases as anticancer agents. For example, the potent activity exhibited by gemcitabine, Ara-C and other related FDA-approved anticancer analogues, has led to numerous structural modifications designed to increase target specificity and potency. Following upon the recent observation that several nucleobase analogues including thiophene-expanded purines, as well as pyrrolo – and thienopyrimidines designed in our laboratories have exhibited selective and highly potent (sub-nanomolar) levels of activity against several key cancers including lung, colon, leukemia, renal, and triple negative breast cancers (among others), we have initiated a program to elucidate their mechanism of action, as well as to further study their highly promising activity in vitro and in vivo. These compounds have advanced to animal studies and as well as investigations to elucidate their mechanism of action.

All of the projects being pursued in the Seley-Radtke laboratories employ structure activity relationship (SAR) algorithms for the biological enhancement of lead compounds. Intimately related to the goals of the drug design projects, synthetic organic research focus includes the discovery of unique strategies to solve design challenges using state of the art techniques for the construction of modified heterocycles, carbohydrates and carbocyclic moieties. In addition, a cross-disciplinary chemical biology approach employs enzymatic assays to survey the effectiveness of the potential drug candidates, as well as to investigate polymerase fidelity with modified nucleotide analogues that possess unique structural advantages for enhanced molecular recognition.

Selected Publications (Last 3 Years)

  1. *Seley-Radtke, K. L. and Yates, M. “The evolution of nucleoside analogue antivirals: a review for chemists and non-chemists. Part 1: early structural modifications to the nucleoside scaffold.” Antiviral Res. 2018, 154, 66-86.
  2. Temburnikar, K.; *Seley-Radtke, K. L.; “Recent advances in synthetic approaches to C-nucleosides”, Beilstein J Org Chem 2018, 14, 772-785.
  3. *Seley-Radtke, K. L. “Flexibility – not just for Yoga!” Antiviral Chem Chemoth, 2018, 26, 1-12.
  4. Eyer, L.; Nencka, R.; de Clercq, E.; Seley-Radtke, K.L.; Růžek, D. “Nucleoside analogues as a rich source of antiviral agents against arthropod-borne flaviviruses”, Antiviral Chem Chemother 2018, 26, 1-28.
  5. Cawrse, B.M.; Lapidus, R.S.; Cooper, B.; Choi, E. Y.; *Seley-Radtke, K.L.; “Antiproliferative Effects of Halogenated Pyrrolo[3,2-d]pyrimidines with Decreased Toxicity Via N5 Substitution.” ChemMedChem 2018, 13, 178-185.
  6. Alzahrani, K. J.; Khandazhinskaya, A. L.; Matyugina, E. S.; Kochetkov, S. N.; *Seley-Radtke, K. L.; *de Koning, H. P; “Evaluation of the antiprotozoan properties of 5’-norcarbocyclic pyrimidine nucleosides” Bioorganic Med Chem Lett 2017, 27, 3081-3086.
  7. Yates, M.; Raje, M.; Chatterjee, Soloveva, V.; Bavari, S.; Seley-Radtke, K. L. “Antiviral Activity for a series of Flex-nucleoside prodrugs against the filoviruses” Bioorg Med Chem Lett 2017, 27, 2800-2802.
  8. Paramonova, M. P.; Khandazhinskaya, A. L.; Seley-Radtke, K. L.; Novikov, M. S. “Synthesis of novel 2-[3-[5-(4-bromophenoxy)pentyl]-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl]-N-arylacetamides as potential antivirals” Mendeleev Communications 2017, 27, 85-87.
  9. Geisman, A. N.; Valuev-Elliston, V. T.; Ozerov, A. A.; Khandazhinskaya, A. L.; Chizhov, A. O.; Kochetkov, S. N.; Pannecouque, C.; Naesens, L.; *Seley-Radtke, K. L.; Novikov, M. S. “1,6-Bis[(benzyloxy)methyl]uracil derivatives – novel antivirals with activity against HIV-1 and influenza H1N1” Bioorg Med Chem, 2016, 24, 2476-2485.
  10. Peters, H. L.; Ku, T. C.; Seley-Radtke, K. L. “Flexibility as a Strategy in Nucleoside Antiviral Drug Design” Curr Med Chem 2015, 22, 3910-3921.
  11. Matugina, E. S.; Novikov, M. S.; Babkov, D. A.; Ozerov, A. A.; Chernousova, L. N.; Andreevskaya, S.; Smirnova, T. G.; Karpenko, I.; Chizhov, A. O.; Muthu, P.; Lutz, S.; Kochetkov, N. S.; *Seley-Radtke, K. L.; Khandazhinskaya, A. L.; “5-Arylaminouracil derivatives: new inhibitors of M. tuberculosis” Chemical Biology & Drug Design 2015, 86, 1387-1396. *corresponding author
  12. Chen, Z.; Ku, T. C.; Seley-Radtke, K. L. “Thiophene-expanded guanosine analogues of Gemcitabine” Bioorg Med Chem Lett. 2015, 25, 4274-4276.
  13. Babkov, D. A.; Khandazhinskaya, A.; Chizhov, A. O.; Andrei, G.; Snoeck, R.; Seley-Radtke, K. L.*, Novikov, M. S. “Toward the Discovery of Dual HCMV-VZV Inhibitors: Synthesis, Structure-Activity Relationship Analysis, and Cytotoxicity Studies of Long Chained 2-Uracil-3-yl-N-(4-phenoxyphenyl)acetamides”. Bioorg Chem Med Chem 2015, 23, 7035-7044. *corresponding author.
  14. Fateev, I. V.; Kharitonova, M. I.; Esipov, R. S.; Antonov, K. V.; Konstantinova, I. D.; Stepanenko, V. N.; Seela, F.; Temburnikar, K. W.; Seley-Radtke, K. L.; Stepchenko, V. A.; Sokolov, Y. A.; Miroshnikov, A. I.; Mikhailopulo, I. A.; “Recognition of the Challenging Heterocyclic Bases by E. coli Purine Nucleoside Phosphorylase versus its Ser90Ala Mutant” Eur. J. 2015, 21, 13146-13156.
  15. Chen, Z.; Jochmans, D.; Ku, T.; Paeshuys, J.; Neyts, J.; Seley-Radtke, K. L. “Bicyclic and tricyclic nucleobase analogues of Sofosbuvir – new scaffolds for Hepatitis C therapies”, ACS Infect. Dis., 2015, 1, 357–366.
  16. Temburnikar, K.; Ross, C.; Wilson, G.; Balzarini, J.; Cawrse, B.; Seley-Radtke, K. L. ” Antiproliferative activities of halogenated pyrrolo[3,2-d]pyrimidines” Bioorg Med Chem 2015, 23, 4354-4363.
  17. Peters, H. L.; Jochman, D.; Posthuma, C. C.; de Wilde, A.; Snijder, E.; Neyts, J.; Seley-Radtke, K. L.; “Design, Synthesis and Anti-coronavirus Activity of a Series of Acyclic Fleximer Analogues” Bioorg Med Chem Lett 2015, 25, 2923-2926.
  18. Babkov, D. A,; Chizhov, A. O,; Khandazhinskaya, A. L.; Corona, A.; Esposito, F.; Tramontano, E.; *Seley-Radtke, K. L.; Novikov, M. S. “An efficient route to novel uracil based drug-like heterocyclesSynthesis 2015, 47,1413-1422. *corresponding author.
  19. Ross, C. R.; Temburnikar, K. W.; Wilson, G. M.; Seley-Radtke; K. L.; “Mitotic Arrest of Breast Cancer MDA-MB-231 Cells by Halogenated Thieno[3,2-d]pyrimidines” Bioorganic Med Chem Lett. 2015, 25, 1715-1717.
  20. Babkov, D. A.; Valuev-Elliston, V. T.; Paramonova, M. P.; Ozerov, A. A.; Ivanov, A. V.; Chizhov, A. O.; Khandazhinskaya, A. L.; Kochetkov, S. N.; Balzarini, J.; Dalemans, D.; Pannecouque, C.; *Seley-Radtke, K. L.; Novikov, M. S. “Scaffold hopping: exploration of acetanilide-containing uracil analogues as potential NNRTIs” Bioorg Med Chem 2015, 23, 1069-1081. *corresponding author

Invited (Peer-reviewed) Book Chapters:

  1. Zimmermann, S. C.; Seley-Radtke, K. L. “Flexible nucleobase analogues. New tools for nucleic acid discoveries”, in RNA Technologies: DNA and RNA Chemical Biology in Science and Medicine, V. A. Erdmann, W. T. Markiewicz and J. Barciszewski eds. Springer, NY, NY 2014, pp 149-165.
  2. Seley, K. L.; Mosley, S. L. “Purine Analogues and Their Role in Methylation and Cancer Chemotherapy” in DNA Methylation and Cancer Therapy, Moshe Szyf, Ed. Landes Bioscience, Georgetown, TX, 2004, Chapter 13, pp 178-186.
  3. Seley, K. L. “Tricyclic Nucleosides Revisited” in Recent Advances in Nucleosides: Chemistry and Chemotherapy, pg. 299-326, C.K. Chu, Ed. Elsevier Science, 2002.
  4. Schneller, S. W.; Seley, K. L.; Hegde, V. R.; Rajappan, V. P. “5′-Norcarbanucleosides in L-Like Configurations” in Recent Advances in Nucleosides: Chemistry and Chemotherapy, pg. 291-297; C.K. Chu, Ed. Elsevier Science, 2002.

 

Honors and Awards

Professional Experience in Higher Education:

2017               Distinguished Visiting Professor, Université d’Orléans, Orléans, France

2017-2018       University System of Maryland Regents’ Professor for Excellent in Research

2015-2018       UMBC Presidential Research Professor

2015-2016       Chair, University Faculty Promotion and Tenure Review Committee (UFRC)

2011-present   Professor, Chemistry & Biochemistry, UMBC, & Joint UMB Biochemistry program

2010-present   Auburn University COSAM Advisory Council member

2009-present   UMBC Honors College Advisory Board member

2008-2010       UMBC Honors Program Faculty Fellow

2007-present   NIH Chemistry Biology Interface Graduate Program, Director and mentor

2007-2008       UMBC President’s Commission on Women, Faculty representative

2005-present   Program in Oncology, Greenebaum Cancer Center, Faculty Member

2005-present   Auburn University Society of Women in Sciences & Mathematics Board Member

2004-2006       UMBC Graduate Summer Bridge Program, Founder & Inaugural Director

2003-present   NIH/UMBC Meyerhoff Minority Graduate & Undergraduate Faculty mentor

2003-present   NSF UMBC MARC U*STAR program, Faculty mentor

2003-2004       NSF UMBC EMBARC (REU) Program, Program Director

2003-2011       Associate Professor, Chemistry & Biochemistry, UMBC

1998-2003       Assistant Professor, Chemistry & Biochemistry, Georgia Institute of Technology

1997-98          Visiting Assistant Professor, Auburn University

1996-98          Postdoctoral Research Fellow, Auburn University

 

Professional Experience other than Higher Education:

2019-2021       Co-Chair, Gordon Research Conference on Nucleosides, Nucleotides & Oligonucleotides

2017-2019       Co-Vice Chair, Gordon Research Conference on Nucleosides, Nucleotides & Oligonucleotides

2019-2023       Secretary, International Society of Nucleosides, Nucleotides & Nucleic Acids (IS3NA)

2018               NIH Special Emphasis Panel – Antimicrobial Therapeutics and Resistance – ZRG1 IDM-Y (82) and 2018/05 ZRG1 IDM-T (07) S, March 28-29 and June 28-29

2018               Session Chair, 7th European Workshop in Drug Synthesis, Siena, Italy, May 24

2018-present   Section Editor, Molecules – Chemical Biology

2018               Special Collections Editor, “Advances in Antiviral Nucleoside Analogues and Their Prodrugs“, Antiviral Chemistry & Chemotherapy

2017               NIH Special Emphasis Panel – Antimicrobial Therapeutics and Resistance ZRG1 IDM-Y (82), Nov 2-3

2017               NIH/NCI ZCA1 SRBK NCI Clinical and Translational R21 & Omnibus R03 review panel, Vice Chair, June 13-14

2017-2019       Immediate Past President, International Society for Nucleosides, Nucleotides & Nucleic Acids (IS3NA)

2017-2019       Chair, Nominations Committee, IS3NA

2017-present   Chair, The Chu Family Foundation awards, International Society of Antiviral Research (ISAR)

2017               Session Chair, Gordon Research Conference on Nucleosides, Nucleotides & Oligonucleotides, Salve Regina University, Newport, RI, June 25-30

2017               Session Chair, 30th International Conference on Antiviral Research, Atlanta, GA, May 21-25

2016-present   Associate Editor, Antiviral Chemistry & Chemotherapy

2016               NIH/NIGMS ZGM1 TRN-Y, Maximizing Investigators Research Awards (MIRA) review panel, Nov 10-11

2016               NIH ZAI1-JRR-M-J3 Rapid Assessment of Zika Virus (ZIKV) Complications review panel, ad hoc member and vice chair, Oct 20

2016               NIH AIDS Discovery & Development of Therapeutics (ADDT) study section, ad hoc member, July 26

2016               NIH F04A-Y(20)L T31/T32 Fellowship study section, ad hoc member, July 13

2016               Session Chair, XXII International Roundtable on Nucleosides, Nucleotides & Nucleic Acids, Paris, France, July 18-21

2016               Session Chair, 6th European Workshop in Drug Synthesis, Siena, Italy, May 17

2016               Session Chair, 5th Antiviral Drugs Research & Development, San Diego, June 1

2016               Conference Committee, 29th International Conference on Antiviral Research, San Diego, CA

2016               Session Chair, 29th International Conference on Antiviral Research, San Diego, CA, April 19

2015-2017       President, International Society on Nucleosides, Nucleotides & Nucleic Acids (IS3NA)

2016-2018       Board of Directors, International Society for Antiviral Research (ISAR)

2016-present   Chair, The Chu Family Women in Science Awards Committee, ISAR

2016-present   Chair, The Chu Family Early Career Awards Committee, IS3NA

2015               NIH/NIGMS ZGM1 TRN-Y, Maximizing Investigators Research Awards (MIRA) review panel

2015-present   Women in Science Scholarship Committee, ISAR

2015-present   UMBC Meyerhoff Program Advisory Board

2015               NIH/NCI ZCA1 SRB-2 Drug Development & Targeting Special Emphasis Panel, Acting Chair

2015               Session Chair, 10th European Workshop in Drug Design, Siena, Italy, May 18-22

2105               Session Chair, 28th International Conference on Antiviral Research, Rome, Italy, May 11-15

2014               Session Chair, 21st International Roundtable on Nucleosides, Nucleotides & Nucleic Acids, August 24-28, Poznan, Poland

2014-present   Program Committee, ISAR

2014               Broadening Experiences in Scientific Training, Advisory Board member, University of Notre Dame Ph.D. program

2014               Session Chair, National ACS Medicinal Chemistry Symposium, Charleston, SC, May 18, 2014

2014               Session Chair, 27th International Conference on Antiviral Research (ICAR), Raleigh, May 12-15

2014               NIH ZRG1 AARR-J PAR Panel: Sustained Release of Antivirals for Treatment or Prevention of HIV, Acting Chair

2013-present   Women in Chemistry Committee, ISAR

2013-2016       Board of Directors, ISAR

2013               NIH/NCI ZCA1 SRLB-2 Exploratory/Developmental Research study section

2013-2014       Vice President, IS3NA

2013-2014       Co-organizer, National ACS Medicinal Chemistry Symposium, Charleston, SC, May 18-21, 2014

2013-2014       Session Chair, National ACS Medicinal Chemistry Symposium, Charleston, SC, May 18-21, 2014

2013-2017       Award Nomination & Selection Committee, ACS Medicinal Chemistry Division

2013               Session Chair, 26th ICAR, San Francisco, May 10-16

2012-present   ISAR Poster Award Committee Chair

2012-present   Editorial Board, Clinical Medicine Insights, Therapeutics

2012               Med Chem Session Chair, 244th National ACS meeting, Philadelphia, PA

2012               Session Chair, 4th European Workshop in Drug Synthesis, May 28, Siena, Italy

2012               Med Chem Session Chair, 243rd National ACS meeting, San Diego, CA

2012               NIH ZRG1 Member Conflict study section (ad hoc)

2011-2013       Editorial Board, Research and Reports in Medicinal Chemistry

2011               Med Chem Session Chair, 242nd National ACS meeting, Denver, CO.

2011               Session Chair, 8th European Workshop in Drug Design, May 22-28, Siena, Italy

2011-present   Associate Editor, Current Protocols in Chemical Biology

2010-2014       NIH AIDS Discovery & Development of Therapeutics (ADDT) study section, member (Vice Chair – 2013-2014)

2010-2012       ACS Div. of Med. Chem. Long Range Planning Committee

2007-2012       Secretary, IS3NA

2010                Session Chair, 19th International Roundtable on Nucleosides, Nucleotides & Nucleic Acids, August 29-Sept 3, 2010, Lyon, France

2009                NSF Chemical Synthesis study section

2008-present    NAS Jefferson Science Fellowship Selection Committee

2008-2012        Scientific Advisory Board, Deszyme Inc.

2008                Session Chair, 12th Indian Society of Chemists & Biologists Int. Conf. on “The Interface of Chemistry-Biology in Biomedical Research“, Pilani, India

2007-present    U.S. Embassy, Moscow Russia, Senior Science Advisor

2007                Women in International Security (WIIS) workshop “Science, Technology and U.S. National Security: Engaging the Next Generation” invited panel member and discussion leader, Washington, DC

 

 Courses Taught

  • CHEM 299: Training in Experimental Chemistry (Cooperative Education)
  • CHEM 351: Organic Chemistry I
  • CHEM 351L: Organic Chemistry Laboratory I
  • CHEM 352: Organic Chemistry II
  • CHEM 352L: Organic Chemistry Laboratory II
  • CHEM 399: Tutorial Projects in Chemistry
  • CHEM 450: Chemistry of Heterocyclic Compounds
  • CHEM 453: Organic Chemistry of Nucleic Acids
  • CHEM 455: Introduction to Biomedicinal Chemistry
  • CHEM 490: Special Topics in Chemistry – Organic Synthetic Methology
  • CHEM 499: Undergraduate Research
  • CHEM 600: Advanced Laboratory Projects
  • CHEM 602: Introduction to Laboratory Research
  • CHEM 650: Chemistry of Heterocyclic Compounds
  • CHEM 653: Organic Chemistry of Nucleic Acids
  • CHEM 654: Organic Synthetic Methodology
  • CHEM 655: Introduction to Biomedicinal Chemistry
  • CHEM 713: Biochemistry/Chemistry Seminar
  • CHEM 715: Issues at the Chemistry/Biology Interface
  • CHEM 898: Pre-Candidacy Doctoral Research
  • CHEM 899: Doctoral Dissertation Research