The use of trifluoromethyl tubercidin as a novel treatment of influenza in an overwhelmed health care setting: a correspondence

Field: Medicine (Health Sciences)

A health care setting represents a wide spectrum of services and places where health care takes place. These settings, for example, include; acute care hospitals, urgent care centers, rehabilitation centers, nursing homes, etc1. These health care settings could be overwhelmed due to more patients, a few health care personnel, lack of essential and comprehensive health care services, like drugs, medical equipment, laboratories, surgical theaters, etc., including social amenities, poor health care environment, as well as limited research studies. Such overwhelmed health care settings will not be able to effectively treat patients with some highly infectious diseases such as tuberculosis, and COVID-19, including influenza1. Over the years, there have been some challenges for an effective treatment of influenza2. The influenza virus has the potential to mutate rapidly, making it difficult to develop effective vaccines and antiviral agents against influenza viruses, causing more morbidities and mortalities among the worldwide population, especially those living in countries with an overwhelmed health care setting2. This is a problem that needs to be investigated and find solutions to. According to the World Health Organization (WHO) estimate, globally 650,000 deaths by respiratory diseases are linked to seasonal influenza each year3. Between 9 and 41 million illnesses, 140,000–710,000 hospitalizations, and 12,000–52,000 deaths were reported annually between the years 2010 and 2020 in the United States alone4. A recent modeling study of influenza-associated mortality estimated there were ~290,000–645,000 deaths per year5. The highest mortality estimates were in sub-Saharan Africa (2.8–16.5 per 100,000 individuals) and southeast Asia (3.5–9.2 per 100,000 individuals). In such overwhelmed health care setting, the challenges of managing influenza become even greater due to the increased demand for care and the limited availability of resources; commonly used antiviral medications can be expensive, creating an additional burden on patients and health care facilities6. We write this correspondence to initiate a discussion regarding the use of a novel agent called trifluoromethyl tubercidin (TMFT) as a novel treatment of influenza and to further explore more research studies on influenza virus in an overwhelmed health care setting, especially those settings in African, Asian, and Latin American regions as we believed that this novel agent would be a breakthrough for easy treatment of influenza among the patients in these countries2,6. The influenza virus uses host cell machinery to modify its own RNA to evade the host's immune system7. Specifically, the virus uses a host enzyme called methyltransferase1 (MTr1) to add a highly methylated modification of the nucleotide guanosine otherwise known as a "cap" to its RNA8. Researchers discovered the high dependence of influenza viruses on MTr1 function. Unlike other viruses, such as SARS-CoV-2, influenza viruses cannot independently add caps to their RNA molecules and instead rely on stealing existing caps making MTr1 activity crucial for influenza virus replication within the cell6,8. In search for inhibitors that specifically target MTr1 and assessing their effect on the amount of virus particles produced in infected tissue, researchers found a breakthrough in the fight against influenza. They discovered a novel derivative of a natural product called TFMT, produced by the bacterium of the genus Streptomyces. This novel agent, has been identified as a potential inhibitor of MTr19, which we believed that it is a promising agent. Both mouse models and human lung tissue preparations were used to test the efficacy of TFMT. Results showed significant reductions in the capping of RNA and protein levels of Influenza A virus (IAV) in normal human bronchial epithelial cells posttreatment without any signs of cytotoxicity on histologic examination. The same study also showed suppression in viral titers in human lung explants indicating potential for clinical translation. While TFMT takes precedence over its predecessor tubercidin in terms of safety profile, it has also demonstrated synergism with other anti-IAV drugs such as baloxavir marboxil (BXM) and oseltamivir suggesting its use as a combination therapy. This possible combination will not only produce greater efficacious yield but also help cut back on the dosage and as a result any potential toxicity that TFMT may induce through long-term targeting of host factors4–8. Sadly, TFMT is not readily available in an overwhelmed health care setting7–9. The discovery of the Streptomyces derivative, TFMT, is a breakthrough in an otherwise overwhelmed health care system constantly in conflict with this evasive virus. The extent of this burden can be illustrated by the findings of a recent study conducted in Vietnam that reported 123,000–200,000 respiratory hospitalizations per year between the years 2014 and 2016, all of which demonstrated influenza as a common cause10. This new treatment, that is; TFMT option holds a promise in the fight against drug-resistant viral mutants of both IAV and Influenza B virus because it targets host mechanisms rather than viral proteins which are subject to constant change. TFMT has also been proven to have synergistic effects with the number of influenza virus particles produced in the tissue compared with other agents like antisense oligonucleotides, RNA interference, and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR/Cas13) systems. It also demonstrates good antiviral potential and little toxicity that may present with problems of feasibility in terms of drug administration and exclusivity in terms of providing only IAV coverage11. Phase I trials would evaluate the safety profile of the drug while phase II and III trials would evaluate its efficacy and safety in patients with confirmed influenza infection.12 Having highlighted some of these breakthroughs in the use of TFMT as a novel treatment of influenza, we, therefore, recommend its adoption in most parts of the world especially in all the overwhelmed health care settings as this would serve as an effective secondary preventive measure for patients with influenza in those settings and further limit complications that could arise from the disease, for example, myocarditis, encephalitis, myositis, rhabdomyolysis, respiratory, and kidney failure3. We also urge the country-men, especially the health authorities living in these overwhelmed health care settings to create more awareness on this novel agent among the physicians and make adequate research provisions for this novel agent in their respective secondary and tertiary health care centers at all cost. This would go a long way to widen the scope and knowledge of the physicians and researchers in facilitating correct diagnosis and treatment of influenza in these settings. Finally, we recommend more clinical trials to be carried out by the clinical researchers and scientists in these health care settings to determine the safety, efficacy, and comparative effectiveness of TFMT in treating influenza. If all these recommendations above are put in place, we strongly believed that there would be a drastically reduction and elimination of influenza viruses in all the overburden health care settings in the world in an effective way. Ethical approval None. Sources of funding None. Author contribution S.S. and A.W.K.: conceptualization. A.A.: funding acquisition. M.O.A.: investigation. S.S.: project administration. S.S. and A.W.K.: resources. A.M.K.: software. M.O.O.: supervision. A.M.K.: validation. M.O.O.: visualization. S.S., A.W.K., A.F., and A.M.K.: writing—original draft. M.O.O. writing—review and editing. S.S.: data curation. Conflict of interest disclosure The authors declare that they have no financial conflict of interest with regard to the content of this report. Research registration unique identifying number(UIN) None. Guarantor Malik Olatunde Oduoye, College of Medical Sciences, Ahmadu Bello University Teaching Hospital, Shika, Kaduna State, Nigeria, and Oli Health Magazine Organization, Kigali, Rwanda. Consent As the information used in this study does not include any identifying information from the patients, written consent from the patients was not required. Provenance and peer review Not commissioned, externally peer reviewed.