Katherine Seley-Radtke

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Katherine Seley-Radtke is an American medicinal chemist who specializes in the discovery and design of novel nucleoside or nucleotide based enzyme inhibitors that may be used to treat infections or cancer. She has authored over 90 peer-reviewed publications,is an inventor of five issued US patents, and is a Professor in the Department of Chemistry & Biochemistry at the University of Maryland, Baltimore County. [1] Her international impact includes scientific collaborations, policy advising and diplomatic appointments in biosecurity efforts.

Contents

Scientific contributions

A pioneer of the "fleximer" class of nucleoside analogs, [2] Seley-Radtke has designed, synthesized and developed a broad range of enzyme inhibitors that have applications as potential therapeutics in treatment of cancer and of infections with viruses. parasites and bacteria. Her lab has identified a series of flexible acyclic nucleosides with prodrug forms which demonstrate activity against coronaviruses, including SARS and MERS, [3] the first known nucleoside analog inhibitors of these viruses. The flexibility of these inhibitors enables binding of the active site as well as amino acid residues outside of the active site which is believed to help reduce emergence of resistance.

A world renowned leader in nucleoside chemistry and in the application of nucleoside analogs to therapeutics, Seley-Radtke has been active in the International Society for Antiviral Research (ISAR), and has organized and chaired a number of Gordon Research Conferences. In addition she actively reviews grant applications for the NIH and has served as co-chair for NIH study sections. She is serving as President-elect, International Society for Antiviral Research (ISAR), [4] has co-chaired two Gordon Research Conferences. Seley-Radtke actively reviews grants for the NIH.

Widely published herself (see "Representative Publications" below), Seley-Radtke is a peer-reviewer for manuscripts submitted for over 60 different scientific publications. She has been an Associate Editor of Antiviral Chemistry & Chemotherapy since 2016 [5] and has served on the editorial boards of Current Protocols in Chemical Biology (Associate Editor); Research and Reports in Medicinal Chemistry (Editorial Board, 2011–2013); Clinical Medicine Insights, and Therapeutics (Editorial Board).

Education

Growing up in Erie, PA, Seley-Radtke pursued science from an early age. Her high school education included a combined program at Gannon University where she carried out a mouse breeding experiment involving over 200 mice in her family home. [6] She graduated from high school at the age of 15. She enrolled in college at Penn State, but only attended college part-time when she married at 18, moved and had two children. She returned to college full-time when her daughters reached junior high, and completed her BA with honors from the University of South Florida in 1992. [7] By then her scientific interests were focused on chemistry and she pursued her PhD in the laboratory of Stewart Schneller, [8] first at USF and then at Auburn University.

International and diplomatic activities

Seley-Radtke has been actively involved in diplomatic efforts between Russia and the US Departments of Health and Human Services and Defense to reduce proliferation threats through scientific collaboration. She served as a Jefferson Fellow of the National Academy of Sciences with a specific assignment in the Office of Cooperative Threat Reduction. [9] Much of her diplomatic work involves addressing scientific issues such as emerging infectious disease threats with Russian leaders. [7] She has worked for the US Dept. of State as a Senior Science advisor, and has served as an advisor on the HHS/DoD Cooperative Threat Reduction (CTR) Program with Russia, Smallpox projects, 2001–2009. [7]

An active leader of international science communities, Seley-Radtke has held various positions on the board of the International Society of Antiviral Research (ISAR) [10] where she is the president elect for 2020–2022. She is also the elected Secretary for the International Society of Nucleosides, Nucleotides & Nucleic Acids (IS3NA), 2019–2023.

Awards and honors

Seley-Radtke has won awards for her teaching and mentoring and her research has established her as an international expert in antiviral chemotherapy. Her work has been recognized with the following awards and honors:

Publications

Seley-Radtke has authored over 90 peer-reviewed publications which have been cited over 1600 times, with an h-index of 22. [17] She is also the inventor on five issued US Patents. [18] Here are some representative publications:

  1. Seley-Radtke K. Discovery, Design, Synthesis, and Application of Nucleoside/Nucleotides. Molecules. 2020;25(7):1526. Published 2020 Mar 27.10.3390/molecules25071526 [19]
  2. Yates MK, Chatterjee P, Flint M, et al. Probing the Effects of Pyrimidine Functional Group Switches on Acyclic Fleximer Analogues for Antiviral Activity. Molecules. 2019;24(17):3184. Published 2019 Sep 2. [20]
  3. Ku T, Lopresti N, Shirley M, et al. Synthesis of distal and proximal fleximer base analogues and evaluation in the nucleocapsid protein of HIV-1. Bioorg Med Chem. 2019;27(13):2883–92. [21]
  4. Seley-Radtke K, Deval J. Advances in antiviral nucleoside analogues and their prodrugs. Antivir Chem Chemother. 2018 Jan–Dec;26:2040206618781410. doi: 10.1177/2040206618781410. PMID   29890841 [22]
  5. Seley-Radtke, Katherine (2018). "Flexibility-Not just for yoga anymore!". Antiviral Chemistry & Chemotherapy. 26:1–12. [3]
  6. Temburnikar K, Seley-Radtke KL. Recent advances in synthetic approaches for medicinal chemistry of C-nucleosides. Beilstein J Org Chem. 2018 Apr 5;14:772–85. [23]
  7. Khandazhinskaya AL, Alexandrova LA, Matyugina ES, Solyev PN, Efremenkova OV, Buckheit KW, Wilkinson M, Buckheit RW Jr, Chernousova LN, Smirnova TG, Andreevskaya SN, Leonova OG, Popenko VI, Kochetkov SN, Seley-Radtke KL. Molecules. Novel 5'-Norcarbocyclic Pyrimidine Derivatives as Antibacterial Agents.2018 Nov 23;23(12):3069. [24]
  8. Cawrse BM, Lapidus RS, Cooper B, Choi EY, Seley-Radtke KL. Anticancer Properties of Halogenated Pyrrolo[3,2-d]pyrimidines with Decreased Toxicity via N5 Substitution. ChemMedChem. 2018;13(2):178–85. [25]
  9. Geisman AN, Valuev-Elliston VT, Ozerov AA, et al. 1,6-Bis[(benzyloxy)methyl]uracil derivatives-Novel antivirals with activity against HIV-1 and influenza H1N1 virus. Bioorg Med Chem. 2016;24(11):2476–85. [26]
  10. Chen Z, Jochmans D, Ku T, Paeshuyse J, Neyts J, Seley-Radtke KL. Bicyclic and Tricyclic "Expanded" Nucleobase Analogues of Sofosbuvir: New Scaffolds for Hepatitis C Therapies. ACS Infect Dis. 2015;1(8):357–66. [27]
  11. Chen Z, Ku TC, Seley-Radtke KL. Thiophene-expanded guanosine analogues of Gemcitabine. Bioorg Med Chem Lett. 2015;25(19):4274–76. [28]
  12. Babkov DA, Valuev-Elliston VT, Paramonova MP, et al. Scaffold hopping: exploration of acetanilide-containing uracil analogues as potential NNRTIs. Bioorg Med Chem. 2015;23(5):1069–81. [29]
  13. Seley-Radtke KL, Sunkara NK. Carbocyclic thymidine analogues for use as potential therapeutic agents. Nucleosides Nucleotides Nucleic Acids. 2009;28(5):633–41. [30]
  14. O'Daniel PI, Jefferson M, Wiest O, Seley-Radtke KL. A computational study of expanded heterocyclic nucleosides in DNA. J Biomol Struct Dyn. 2008;26(3):283–92. [31]
  15. Katherine L Seley, Liang Zhang, Asmerom Hagos, and Stephen Quirk. Fleximers: design and synthesis of a new class of novel shape-modified nucleosides. Journal of Organic Chemistry, 2002 67 (10), 3365–73. [2]

Related Research Articles

Nucleotide Biological molecules that form the building blocks of nucleic acids

Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules within all life-forms on Earth. Nucleotides are obtained in the diet and are also synthesized from common nutrients by the liver.

Nucleobase Nitrogen-containing biological compounds that form nucleosides

Nucleobases, also known as nitrogenous bases or often simply bases, are nitrogen-containing biological compounds that form nucleosides, which, in turn, are components of nucleotides, with all of these monomers constituting the basic building blocks of nucleic acids. The ability of nucleobases to form base pairs and to stack one upon another leads directly to long-chain helical structures such as ribonucleic acid (RNA) and deoxyribonucleic acid (DNA). Five nucleobases—adenine (A), cytosine (C), guanine (G), thymine (T), and uracil (U)—are called primary or canonical. They function as the fundamental units of the genetic code, with the bases A, G, C, and T being found in DNA while A, G, C, and U are found in RNA. Thymine and uracil are distinguished by merely the presence or absence of a methyl group on the fifth carbon (C5) of these heterocyclic six-membered rings. In addition, some viruses have aminoadenine (Z) instead of adenine. It differs in having an extra amine group, creating a more stable bond to thymine.

Nucleoside Any of several glycosylamines comprising a nucleobase and a sugar molecule

Nucleosides are glycosylamines that can be thought of as nucleotides without a phosphate group. A nucleoside consists simply of a nucleobase and a five-carbon sugar whereas a nucleotide is composed of a nucleobase, a five-carbon sugar, and one or more phosphate groups. In a nucleoside, the anomeric carbon is linked through a glycosidic bond to the N9 of a purine or the N1 of a pyrimidine. Nucleotides are the molecular building-blocks of DNA and RNA.

A nucleoside triphosphate is a molecule containing a nitrogenous base bound to a 5-carbon sugar, with three phosphate groups bound to the sugar. It is an example of a nucleotide. They are the molecular precursors of both DNA and RNA, which are chains of nucleotides made through the processes of DNA replication and transcription. Nucleoside triphosphates also serve as a source of energy for cellular reactions and are involved in signalling pathways.

Vidarabine

Vidarabine or 9-β-D-arabinofuranosyladenine (ara-A) is an antiviral drug which is active against herpes simplex and varicella zoster viruses.

An antimetabolite is a chemical that inhibits the use of a metabolite, which is another chemical that is part of normal metabolism. Such substances are often similar in structure to the metabolite that they interfere with, such as the antifolates that interfere with the use of folic acid; thus, competitive inhibition can occur, and the presence of antimetabolites can have toxic effects on cells, such as halting cell growth and cell division, so these compounds are used as chemotherapy for cancer.

Nucleoside analogue Biochemical compound

Nucleoside analogues are nucleosides which contain a nucleic acid analogue and a sugar. Nucleotide analogs are nucleotides which contain a nucleic acid analogue, a sugar, and a phosphate group with one to three phosphates.

Taribavirin Antiviral drug

Taribavirin is an antiviral drug in Phase III human trials, but not yet approved for pharmaceutical use. It is a prodrug of ribavirin, active against a number of DNA and RNA viruses. Taribavirin has better liver-targeting than ribavirin, and has a shorter life in the body due to less penetration and storage in red blood cells. It is expected eventually to be the drug of choice for viral hepatitis syndromes in which ribavirin is active. These include hepatitis C and perhaps also hepatitis B and yellow fever.

Tiazofurin

Tiazofurin is a drug which acts as an inhibitor of the enzyme IMP dehydrogenase. Tiazofurin and its analogues were under investigation for potential use in the treatment of cancer, though side effects such as pleuropericarditis and a flu-like syndrome precluded further development. They also show antiviral effects and may be reevaluated as potential options in the treatment of newly emerging viral diseases.

Deoxycytidine kinase

Deoxycytidine kinase (dCK) is an enzyme which is encoded by the DCK gene in humans. dCK predominantly phosphorylates deoxycytidine (dC) and converts dC into deoxycytidine monophosphate. dCK catalyzes one of the initial steps in the nucleoside salvage pathway and has the potential to phosphorylate other preformed nucleosides, specifically deoxyadenosine (dA) and deoxyguanosine (dG), and convert them into their monophosphate forms. There has been recent biomedical research interest in investigating dCK's potential as a therapeutic target for different types of cancer.

Diarylpyrimidines

Diarylpyrimidines (DAPY) and diaryltriazines (DATA) are two closely related classes of molecules resembling the pyrimidine nucleotides found in DNA. They show great potency in inhibiting the activity of HIV reverse transcriptase. Several compounds in this class are non-nucleoside reverse transcriptase inhibitors used clinically in the treatment of HIV/AIDS, notably etravirine and rilpivirine.

Pyrimidine analogues are antimetabolites which mimic the structure of metabolic pyrimidines.

Discovery and development of nucleoside and nucleotide reverse-transcriptase inhibitors began in the 1980s when the AIDS epidemic hit Western societies. NRTIs inhibit the reverse transcriptase (RT), an enzyme that controls the replication of the genetic material of the human immunodeficiency virus (HIV). The first NRTI was zidovudine, approved by the U.S. Food and Drug Administration (FDA) in 1987, which was the first step towards treatment of HIV. Six NRTI agents and one NtRTI have followed. The NRTIs and the NtRTI are analogues of endogenous 2´-deoxy-nucleoside and nucleotide. Drug-resistant viruses are an inevitable consequence of prolonged exposure of HIV-1 to anti-HIV drugs.

Carbocyclic nucleoside Class of chemical compounds

Carbocyclic nucleosides are nucleoside analogues in which a methylene group has replaced the oxygen atom of the furanose ring. These analogues have the nucleobase attached at a simple alkyl carbon rather than being part of a hemiaminal ether linkage. As a result, they have increased chemical stability. They also have increased metabolic stability because they are unaffected by phosphorylases and hydrolases that cleave the glycosidic bond between the nucleobase and furanose ring of nucleosides. They retain many of the biological properties of the original nucleosides with respect to recognition by various enzymes and receptors.

MK-608

MK-608 is an antiviral drug, an adenosine analog. It was originally developed by Merck & Co. as a treatment for hepatitis C, but despite promising results in animal studies, it was ultimately unsuccessful in clinical trials. Subsequently it has been widely used in antiviral research and has shown activity against a range of viruses, including Dengue fever, tick-borne encephalitis virus, poliovirus, and most recently Zika virus, in both in vitro and animal models. Since it has already failed in human clinical trials previously, it is unlikely MK-608 itself will be developed as an antiviral medication, but the continuing lack of treatment options for these emerging viral diseases means that much research continues using MK-608 and related antiviral drugs.

NS5B inhibitor

Non-structural protein 5B (NS5B) inhibitors are a class of direct-acting antivirals widely used in the treatment of chronic hepatitis C. Depending on site of action and chemical composition, NS5B inhibitors may be categorized into three classes—nucleoside active site inhibitors (NIs), non-nucleoside allosteric inhibitors, and pyrophosphate analogues. Subsequently, all three classes are then subclassified. All inhibit RNA synthesis by NS5B but at different stages/sites resulting in inability of viral RNA replication. Expression of direct-acting NS5B inhibitors does not takes place cells that are not infected by hepatitis C virus, which seems to be beneficial for this class of drugs.

GS-6620

GS-6620 is an antiviral drug which is a nucleotide analogue. It was developed for the treatment of Hepatitis C but while it showed potent antiviral effects in early testing, it could not be successfully formulated into an oral dosage form due to low and variable absorption in the intestines which made blood levels unpredictable. It has however continued to be researched as a potential treatment for other viral diseases such as Ebola virus disease.

EICAR (antiviral) Chemical compound

EICAR is a drug which acts as an inhibitor of the enzyme IMP dehydrogenase. It is a nucleoside derivative which has both anti-cancer and antiviral effects, and was originally developed for the treatment of leukemia, but was unsuccessful in human clinical trials. It has broad spectrum antiviral effects with activity against pox viruses, Semliki forest virus, Junin virus, reovirus, influenza, measles virus and respiratory syncytial virus among others, although it is not active against coronaviridae such as SARS-CoV-1. This useful spectrum of activity means that EICAR and related derivatives continue to be investigated for the treatment of viral diseases.

Valopicitabine

Valopicitabine (NM-283) is an antiviral drug which was developed as a treatment for hepatitis C, though only progressed as far as Phase III clinical trials. It acts as a RNA-dependent RNA polymerase inhibitor. It is a prodrug which is converted inside the body to the active form, 2'-C-methylcytidine triphosphate.

The International Society for Antiviral Research (ISAR) is a scientific society that focuses on the discovery and clinical application of antiviral agents. It was founded in 1987 to encourage the exchange of information and collaborative research on the development of antiviral, biological and chemical agents.

References

  1. ↑ "UMBC Dept of Chemistry & Biochemistry website for Professor Katherine L. Seley-Radtke".
  2. 1 2 Seley, Katherine L; Zhang, Liang; Hagos, Asmerom; Quirk, Stephen (2002). ""Fleximers". Design and Synthesis of a New Class of Novel Shape-Modified Nucleosides 1". The Journal of Organic Chemistry. 67 (10): 3365–73. doi:10.1021/jo0255476. ISSN   0022-3263. PMID   12003548.
  3. 1 2 Seley-Radtke, Katherine (2018). "Flexibility—Not just for yoga anymore!". Antiviral Chemistry and Chemotherapy. 26: 204020661875678. doi:10.1177/2040206618756788. ISSN   2040-2066. PMC   5890542 . PMID   29466861.
  4. ↑ "IS3NA".
  5. ↑ "Antiviral Chemistry and Chemotherapy editorial board". 27 October 2015.
  6. ↑ "ISAR News" (PDF).
  7. 1 2 3 "Auburn University, COSAM member spotlight".
  8. ↑ "Schneller Group at Auburn University".
  9. ↑ "Office of Cooperative Threat Reduction in the Bureau of International Security and Nonproliferation".
  10. ↑ "International Society of Antiviral Research".
  11. ↑ "ISAR 2020 ward Recipients".
  12. ↑ "USMBC regents awards".
  13. ↑ "Maryland Chemist of the Year, UMBC news". 12 January 2017.
  14. ↑ "USMBC award news".
  15. ↑ "University of South Florida Chemistry News, Spring 2015" (PDF).
  16. ↑ "ISAR 2020 Award recipients".
  17. ↑ "Katherine Seley-Radtke - Google Scholar". scholar.google.com. Retrieved 2020-07-21.
  18. ↑ "US Patent Office Issued patents for Katherine Radtke".
  19. ↑ Seley-Radtke, Katherine (2020-03-27). "Discovery, Design, Synthesis, and Application of Nucleoside/Nucleotides". Molecules. 25 (7): 1526. doi: 10.3390/molecules25071526 . ISSN   1420-3049. PMC   7181063 . PMID   32230805.
  20. ↑ Yates, Mary K; Chatterjee, Payel; Flint, Mike; Arefeayne, Yafet; Makuc, Damjan; Plavec, Janez; Spiropoulou, Christina F; Seley-Radtke, Katherine L (2019-09-02). "Probing the Effects of Pyrimidine Functional Group Switches on Acyclic Fleximer Analogues for Antiviral Activity". Molecules. 24 (17): 3184. doi: 10.3390/molecules24173184 . ISSN   1420-3049. PMC   6749450 . PMID   31480658.
  21. ↑ Ku, Therese; Lopresti, Natalie; Shirley, Matthew; Mori, Mattia; Marchant, Jan; Heng, Xiao; Botta, Maurizio; Summers, Michael F; Seley-Radtke, Katherine L. (2019). "Synthesis of distal and proximal fleximer base analogues and evaluation in the nucleocapsid protein of HIV-1". Bioorganic & Medicinal Chemistry. 27 (13): 2883–92. doi:10.1016/j.bmc.2019.05.019. PMC   6556414 . PMID   31126822.
  22. ↑ Seley-Radtke, Katherine; Deval, Jerome (2018). "Advances in antiviral nucleoside analogues and their prodrugs". Antiviral Chemistry & Chemotherapy. 26: 2040206618781410. doi:10.1177/2040206618781410. ISSN   2040-2066. PMC   6024498 . PMID   29890841.
  23. ↑ Temburnikar, Kartik; Seley-Radtke, Katherine L (2018). "Recent advances in synthetic approaches for medicinal chemistry of C-nucleosides". Beilstein Journal of Organic Chemistry. 14: 772–85. doi:10.3762/bjoc.14.65. ISSN   1860-5397. PMC   5905277 . PMID   29719574.
  24. ↑ Khandazhinskaya, Anastasia; Alexandrova, Liudmila; Matyugina, Elena; Solyev, Pavel; Efremenkova, Olga; Buckheit, Karen; Wilkinson, Maggie; Buckheit, Robert; Chernousova, Larisa; Smirnova, Tatiana; Andreevskaya, Sofya (2018-11-23). "Novel 5′-Norcarbocyclic Pyrimidine Derivatives as Antibacterial Agents". Molecules. 23 (12): 3069. doi: 10.3390/molecules23123069 . ISSN   1420-3049. PMC   6321083 . PMID   30477147.
  25. ↑ Cawrse, Brian M; Lapidus, Rena S; Cooper, Brandon; Choi, Eun Yong; Seley-Radtke, Katherine L. (2018-01-22). "Anticancer Properties of Halogenated Pyrrolo[3,2- d ]pyrimidines with Decreased Toxicity via N5 Substitution". ChemMedChem. 13 (2): 178–85. doi:10.1002/cmdc.201700641. PMC   5912934 . PMID   29193845.
  26. ↑ Geisman, Alexander N; Valuev-Elliston, Vladimir T; Ozerov, Alexander A; Khandazhinskaya, Anastasia L; Chizhov, Alexander O; Kochetkov, Sergey N; Pannecouque, Christophe; Naesens, Lieve; Seley-Radtke, Katherine L; Novikov, Mikhail S. (2016). "1,6-Bis[(benzyloxy)methyl]uracil derivatives—Novel antivirals with activity against HIV-1 and influenza H1N1 virus". Bioorganic & Medicinal Chemistry. 24 (11): 2476–85. doi:10.1016/j.bmc.2016.04.010. PMID   27112451.
  27. ↑ Chen, Zhe; Jochmans, Dirk; Ku, Therese; Paeshuyse, Jan; Neyts, Johan; Seley-Radtke, Katherine L. (2015-08-14). "Bicyclic and Tricyclic "Expanded" Nucleobase Analogues of Sofosbuvir: New Scaffolds for Hepatitis C Therapies". ACS Infectious Diseases. 1 (8): 357–66. doi:10.1021/acsinfecdis.5b00029. ISSN   2373-8227. PMID   27624884.
  28. ↑ Chen, Zhe; Ku, Therese C; Seley-Radtke, Katherine L (2015). "Thiophene-expanded guanosine analogues of Gemcitabine". Bioorganic & Medicinal Chemistry Letters. 25 (19): 4274–76. doi:10.1016/j.bmcl.2015.07.086. PMC   4579529 . PMID   26316465.
  29. ↑ Babkov, Denis A; Valuev-Elliston, Vladimir T; Paramonova, Maria P; Ozerov, Alexander A; Ivanov, Alexander V; Chizhov, Alexander O; Khandazhinskaya, Anastasia L; Kochetkov, Sergey N; Balzarini, Jan; Daelemans, Dirk; Pannecouque, Christophe. (2015). "Scaffold hopping: Exploration of acetanilide-containing uracil analogues as potential NNRTIs". Bioorganic & Medicinal Chemistry. 23 (5): 1069–81. doi:10.1016/j.bmc.2015.01.002. PMID   25638501.
  30. ↑ Seley-Radtke, Katherine L; Sunkara, Naresh K (2009-08-11). "Carbocyclic Thymidine Analogues for Use as Potential Therapeutic Agents". Nucleosides, Nucleotides and Nucleic Acids. 28 (5–7): 633–641. doi:10.1080/15257770903091920. ISSN   1525-7770. PMC   3701155 . PMID   20183606.
  31. ↑ O'Daniel, Peter I; Jefferson, Malcolm; Wiest, Olaf; Seley-Radtke, Katherine L. (2008). "A Computational Study of Expanded Heterocyclic Nucleosides in DNA". Journal of Biomolecular Structure and Dynamics. 26 (3): 283–92. doi:10.1080/07391102.2008.10507243. ISSN   0739-1102. PMC   2593457 . PMID   18808194.
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