Office: CHEM 405C
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)
- *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.
- Temburnikar, K.; *Seley-Radtke, K. L.; “Recent advances in synthetic approaches to C-nucleosides”, Beilstein J Org Chem 2018, 14, 772-785.
- *Seley-Radtke, K. L. “Flexibility – not just for Yoga!” Antiviral Chem Chemoth, 2018, 26, 1-12.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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
- Chen, Z.; Ku, T. C.; Seley-Radtke, K. L. “Thiophene-expanded guanosine analogues of Gemcitabine” Bioorg Med Chem Lett. 2015, 25, 4274-4276.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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 heterocycles” Synthesis 2015, 47,1413-1422. *corresponding author.
- 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.
- 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:
- 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.
- 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.
- Seley, K. L. “Tricyclic Nucleosides Revisited” in Recent Advances in Nucleosides: Chemistry and Chemotherapy, pg. 299-326, C.K. Chu, Ed. Elsevier Science, 2002.
- 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
- 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