James K. Bashkin
University of Missouri-Saint Louis, United States
Scientific Tracks Abstracts: J Med Chem
The current study investigates the application of pyrrole-imidazole polyamides to fighting viral diseases in cell and tissue culture. We first reported the use of polyamides against high-risk human papillomavirus (HPV) types 16, 18 and 31 in 2011. A previous report on repressing latency of HIV with polyamides had appeared from the Dervan group in 2004, while inhibition of Maloney murine leukemia virus integration with the same class of molecules was reported the previous year, and so-called "Paradoxical effects," meaning the authors did not understand their observations, were reported in for effects of polyamides on HLTV-1 transcription by the same group in 2004. Through extensive molecular biology and biophysical studies (with Professor Cynthia M. Dupureur and group), we have explained the "paradoxical effects" and find these rule-breaking effects to be the basis of our observed antiviral activity. We have shown the "rules" for DNA recognition by polyamides reported so widely by Dervan et al. do not apply to longer molecules, where enthalpy plays no role in the free energy of binding, and entropy likely associated with deaggregation of polyamides is the determining factor in providing favorable, negative Gibbs free energies of binding. This deaggregation appears to be aided by increasing the positive charge on both the C- and N-termini of polyamides, resulting in improved antiviral parameters (IC50 and IC90) and improved thermodynamic binding parameters such as the dissociation constants. We now have IC50 values as low as 8-13nM. Of interest to medicinal and pharmaceutical chemists, our polyamides were predicted by many to be incapable of entry into cells. However, the opposite is usually the case, and active uptake is often the reason, though we have not identified the specific uptake mechanism yet. Uptake into some cells is extremely effective, including essentially primary keratinocytes infected with episomal HPV. Another example is a range of blood cells: iv pharmacokinetics are hampered by the immediate uptake of compounds into blood cells, leaving none in the plasma to be measured and making bioavailability, by definition, zero, even though the blood cells transport the compounds to internal organs such as bone marrow, liver and spleen.
James Bashkin, D.Phil. was born in Iowa City, Iowa. He started as a Biology student at the University of Arizona and graduated from the University of Calfornia-Irvine with a Chemistry degree in 1977, Where upon he enrolled in the doctoral program at the University of Oxford, U.K. In 1982, he completed his studies in organometallic chemistry under Malcolm L.H. Green and joined the lab of R. H. Holm at Harvard University for postdoctoral and NIH postdoctoral work on bioinorganic chemistry. In 1985, he joined Monsanto Corporate research where he published a variety of papers ranging from RNA chemistry to commodity organic synthesis and received several awards for green chemistry. In 1991, he joined the faculty of Washington University in St. Louis and in 1999 he returned to Monsanto.After the transitions to Pharmacia and Pfizer, he co-founded the antiviral company NanoVir, LLC with virologist Chris Fisher and began work at the University ofm Missouri-St. Louis. In 2011, he was appointed full professor and in 2022 received the St. Louis Award from the local section of the American Chemical Society. He published 80 papers and has 16 issued U.S. patents.
Medicinal Chemistry received 6627 citations as per Google Scholar report
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