James K Bashkin completed his D.Phil. at the age of 24 years from Oxford University and postdoctoral studies from Harvard University’s Department of Chemistry. He is Professor of Chemistry and Biochemistry at the University of Missouri-St. Louis and Co-Founder and Director of Chemistry at NanoVir LLC, an antiviral company. He also worked at Monsanto, Pharmacia, and Pfizer, has published more than 73 papers in reputed journals, and has served as an editorial board member and/or associate editor of numerous journals, most notably as an Editorial Advisory Board member of Chemical Reviews from 1991-2014.
Approximately 5,000 women die each year in the US from cervical cancer, and the worldwide mortality is 300,000 per year, yet this is only one type of cancer caused by human papillomavirus (HPV). In addition to the broad use of vaccines, anti-HPV drugs are needed for those who are already infected. Off-label, non-blinded clinical studies performed with formulations of the active pharmaceutical ingredient chloroquine, a well-known antimalarial, showed strong anti-HPV activity and restored normal skin tissue health to patients with both high- and low-risk HPV diseases. Confirmation of specific anti-HPV activity in cell culture was obtained by studies in three independent laboratories via the National Institutes of Health. We present cell data and before and after data from patients with a range of high- and low-risk HPV infections, including orphan diseases. Successful treatment includes patients with Bowen’s disease, oral papillomas, cervical intraepithelial neoplasia (CIN) grades I and II, and genital warts. In several cases, independent labs ran DNA tests that showed no evidence of HPV after treatment with topical chloroquine formulations. Patients were treated in the US, Nigeria, China, and other locations, with nearly one hundred patients undergoing treatment to date. Chloroquine and related molecules have been found to reactivate p53 expression in tumors, leading to tumor shrinkage by autophagy and related processes, and this has led the antimalarial class to be studied as anticancer drugs in eight or more clinical trials, some reaching Phase III. We suspect that the importance of eliminating p53 as part of the HPV lifecycle, as carried out by the viral E6 oncoprotein which ubiquitinates p53, and the documented recovery of p53 expression in tumors caused by chloroquine, play a role in the observed patient results. Patient data will be shown after the ten day to two-week topical treatment course via a cream, douche, or mouthwash. Drug development is currently underway to gain FDA approval of chloroquine formulations as treatments for a wide range of HPV-derived diseases, allowing it to prevent cervical and other cancers and to eliminate genital, oral, laryngeal, and other papillomas that plague the general population and orphan population groups. We are also pursuing the mechanism of action to provide details at the molecular level.
Maud Bollenbach joined the Balskus Lab in the summer of 2017 as a postdoc fellow after obtaining her PhD in Chemistry from the University of Strasbourg. As a graduate student, she worked under the supervision of Drs. Jean-Jacques Bourguignon and Martine Schmitt, and her research focused on the development of small molecules for the treatment of neuropathic pain. In the Balskus Lab, Maud is designing inhibitors of gut microbial TMA generation, which can be involved in human pathologies.
The human body is colonized by trillions of microorganisms (the human microbiota), the majority of which are present in the gut. These microorganisms can produce a wide variety of small-molecule metabolites that may influence host health. Indeed, metabolomics experiments have showed strong correlations between levels of human serum metabolites made or modified by gut microbes and both health and disease states. Anaerobic choline metabolism by gut microbes exemplifies the challenges involved in studying microbial activities. While choline is an essential nutrient for the host (contributing to cell membrane function, methyl transfer events and neurotransmission), its conversion into trimethylamine (TMA) by the gut microbiota is implicated in a number of diseases, including nonalcoholic fatty liver disease, cardiovascular disease, chronic kidney disease and trimethylaminuria (fish malodor syndrome). The correlation between microbial choline metabolism and disease, as well as its prevalence in the human gut microbiota, make this metabolic activity a prominent target for manipulation and further study. Our group recently discovered and biochemically characterized the central TMA-generating enzyme choline-TMA lyase (CutC).1,2 In collaboration with Prof. Catherine Drennan’s group, we also have been able to co-crystallize CutC with its substrate choline.2 By identifying key active site residues involved in binding and catalysis, we have been able to rationally design choline analogs. These molecules were tested for inhibition of anaerobic choline metabolism by the cut gene cluster-containing human gut isolate Escherichia coli MS 200-1. Betaine aldehyde emerged as promising inhibitor (EC50 = 0.4 mM).3 We also showed its efficacy against additional Gram-positive (Clostridium sporogenes ATCC 1559) and Gram-negative (Proteus mirablis BB2000, Escherichia coli MS 69-1, Klebsiella sp. MS 93-2), with EC50s values ranging from 1 to 5 mM. Finally betaine aldehyde inhibited the conversion of choline to TMA by a human fecal suspension ex vivo, confirming its efficacy in a complex setting more reminiscent of the gut microbiota.