Published March 5, 2023 | Version v1
Journal article Open

Tucaresol: A Unique Oral Candidate Drug Ideally Accessible for Treatment of Covid-19 Disease

Authors/Creators

  • 1. CoFounder, ChemThera Sciences, Cornwall, Ontario, Canada.
  • 2. CoFounder, ChemThera Sciences, Laval, Quebec, Canada.
  • 3. Senior Manager, Process & Development, ChemThera Sciences, Saint-Jerome, Quebec, Canada.

Description

The SARS-CoV-2 pandemic has significantly impacted world health and economic status. In response, much work has been undertaken to provide effective, safe vaccines, antibodies and antiviral drugs with which to address this pandemic. Treatment of a pandemic population presents multiple challenges in addition to the primary issue of drug efficacy and safety, such as large scale drug manufacture and distribution, drug stability, oral dosing and pharmacoeconomic considerations. Ideally, these factors must be addressed if new candidate drugs are to be advanced for treatment of large (pandemic) populations. Subsequently, new antivirals have reached the market but choices are few. According to the NIH Covid Treatment Guidelines, only three small molecule antiviral drugs are available to treat Covid-19 disease. As such, a significant part of the research towards discovery of new antiviral drugs has focused on screening and evaluation of ‘repurposed drugs’ or previously approved or clinical stage drugs. Yet, in spite of this increased research activity, one promising clinical stage candidate drug has received little attention regarding its potential as a monotherapy or component of combination therapy for treatment of Covid-19 disease. Tucaresol, with documented human safety and pharmacokinetic data, is an orally active, stable, small molecule amenable to large scale manufacture by a proprietary two-step synthesis developed by us. Tucaresol functions as a host-targeted antiviral by selective  protection/reconstitution of CD4+ T helper cells as demonstrated in HIV patients and SIV macaques. In view of similarities between HIV and SARS-CoV-2, especially with respect to host CD4+ T helper cells, and the suitability of Tucaresol for facile treatment of pandemic populations, Tucaresol is presented herein for treatment of mild-to-moderate Covid-19 patients but may also be useful for treatment of advanced disease accompanied by lymphopenia.

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References

  • Dunleavy, K. (2022). Pfizer Reveals Plan to Make its Products Available to 45 Poor Countries at Not-for-Profit Cost. FIERCE Pharma, May 25, 2022.
  • Becker, Z.,Dunleavy, K., Kansteiner, F. and Liu, A. (2022). COVID-19 Tracker. FIERCE Pharma, August 12, 2022.
  • Bendix, A. (2022). As More People Report Covid Rebounds After Paxlovid, Experts Insist Cases are Rare. NBC News, July 27, 2022.
  • Collins, K.C., Schlosburg, J.E., Lockner, J.W., Bremer, P.T., Ellis, B.A. and Janda, K.D. (2014). Lipid Tucaresol as an Adjuvant for Methamphetamine Vaccine Development. Chem Commun (Camb). April 21;50(31), 4079-81.
  • Conway, J.M. and Perelson, A.S. (2015). Post-Treatment Control of HIV Infection. Proc. Natl. Acad. Sci, U.S.A.. April 13, 2015; 112(17), 5467-5472.
  • Coronavirus (COVID-19) Update: FDA Authorizes Additional Oral Antiviral for Treatment of COVID-19 in Certain Adults. FDA News Release, December 23, 2021.
  • Coronavirus (COVID-19) Update: FDA Authorizes Additional Oral Antiviral for Treatment of COVID-19 December 23, 2021.
  • Davanzo, G.G., Codo, A.C., Brunetti, N.S., Boldrini, V., Knittel, T.L., Monterio, L.B., De Moraes, D., Ferrari, A.J.R., De Souza, G.F., Muraro, S.P. et al. (2020). SARS-CoV-2 uses CD4 to Infect T Helper Lymphocytes. MedRxiv, https://doi.org/10.1101/2020.09.25.20200329.
  • Dunleavy, K. (2022). FDA Wants Pfizer to Study COVID Rebound Cases With a Longer Course of Paxlovid. FIERCE Pharma., August 22, 2022.
  • Dunleavy, K. (2022). Gilead Touts Analysis Showing COVID Antiviral Veklury Performs Best When Given Early In Illness. FIERCE Pharma. April 25, 2022.
  • Dunleavy, K. (2022). Pfizer Reveals Plan to Make its Products Available to 45 Poor Countries at not-for-Profit Cost. FIERCE Pharma, May 25, 2022.
  • Gligorijevic, N., Radomirovic, M., Nedic, O., Stojadinovic, M., Khulal, U., Stanic-Vucinic, D., Velickovic, T.C. (2021). Molecular Mechanisms of Possible Action of Phenolic Compounds in COVID-19 Protection and Prevention. Intl. J. Mol. Sci., 22(22), 12385. doi: 10.3390/ijms222212385.
  • Gori, A., Trabattori, D., Bandera, A., Sarsella, M., Marchetti, G., Gazzola, L., Biasin, M., Rhodes, J., McDade, H., Panebianco, R. et al. (2004). Immunomodulation Induced by Tucaresol in HIV Infection: Results of a 16 Week Pilot Phase I/II trial. Antivir. Ther. , 9(4), 603-614.
  • Havlir, D.V., Hellmann, N.S., Petropoulos, C.J., Whitcomb, J.M., Collier, A.C., Hirsch, M.S., Tebas, P., Sommadossi, J.P. and Richman, D.D. (2000). Drug Susceptibility in HIV Infection After Viral Rebound in Patients Receiving Indinavir-Containing Regimens. JAMA, 283(2), 229-234.
  • Jang, W.D., Jeon, S., Kim, S. and Lee, S.P. (2021). Drugs repurposed for COVID-19 by Virtual Screening of 6218 Drugs and Cell-Based Assay. Proc. Natl. Acad. Sci. U.S.A., 118(30), e2024302118.
  • Kabinger, F., Stiller, C., Schmitzová, J., Dienemann, C., Kokic, G., Hillen, H.S., Höbartner, C. and Cramer, P. (2021). Mechanism of Molnupiravir-induced SARS-CoV-2 Mutagenesis. Nat. Struct. Mol. Biol., 28(9), 740-746.
  • Kansteiner, F. (2022). Paxlovid's Post-Exposure Protection Flop Hardly Spells The End for Pfizer's COVID Franchise: Analysts. FIERCE Pharma, May 2, 2022.
  • Lowe, D. (2022). Paxlovid Resistance: Is It Just A Matter Of Time Now? Science, July 11, 2022.
  • Lu, L., Zhang, H., Dauphars, D.J., He, Y.W. (2021). A Potential Role of Interleukin 10 in COVID-19 Pathogenesis. Trends Immunol., 42(1), 3-5. doi: 10.1016/j.it.2020.10.012.
  • National Library of Medicine (U.S.). (2004-2008). Tucaresol as Add-on to HAART (Highly Active Antiretroviral Therapy) In Chronic HIV-1 Infected Adults. Identifier NCT00343941. https:// clinicaltrials.gov/ct2/show/ NCT00343941
  • Notice Regarding The Media Coverage About S-217622, A Therapeutic Drug for COVID-19. Press Release. April 13, 2022.
  • Peck, R.W., Wootton, R., Wiggs, R., Layton, G. and Posner, J. (1998). Effect of Food and Gender on the Pharmacokinetics of Tucaresol In Healthy Volunteers. Br. J. Clin. Pharmacol., 46(1), 83-86.
  • Peng, X., Ouyang, J., Isnard, S., Lin, J., Fombuena, B., Zhu, B. and Routy, J.P. (2020). Sharing CD4 + T cell loss: when COVID-19 and HIV Collide on Immune System. Front. Immunol., https://doi.org/10.3389/ fimmu.2020.596631
  • Rhodes, J., Chen, H,. Hall, S.R., Beesley, J.E., Jenkins, D.C., Collins, P. and Zheng, B. (1995). Therapeutic Potentiation of the Immune System By Costimulatory Schiff-Base-Forming Drugs. Nature, 337(6544), 71-75.
  • Riva, L., Yuan, S., Xin, Y., Martin-Sancho, L., Matsunaga, N., Pache, L., Burgstaller-Muehlbacher, S., De Jesus P.D., Teriete, P., et al. (2020). Discovery of SARS-CoV-2 Antivirals Through Large Scale Drug Repositioning. Nature, 586(7827), 113-119.
  • Robinson, P.C., Liew, D.F.L., Tanner, H.L., Grainger, J.R., Dwek, R.A., Reisler, R.B., Steinman, L., Feldmann, M., Ho, L.P., Hussell, T., et al. (2022). COVID-19 Therapeutics: Challenges and Directions for the Future. Proc. Natl. Acad. Sci. U.S.A., 119(15): e2119893119. https://doi.org/10.1073/pnas.2119893119
  • Rolan, P.E., Mercers A.J., Wootton, R. and Posner, J. (1995). Pharmacokinetics and Pharmacodynamics of Tucaresol, an Antisickling Agent In Healthy Volunteers. Br. J. Clin. Pharmacol., 39(4), 375-380.
  • Rolan, P.E., Parker, J.E., Gray, S.J., Weatherley, B.C., Ingram, J., Leavens, W., Wootton, R. and Posner, J. (1993). The Pharmacokinetics, Tolerability, And Pharmacodynamics of Tucaresol (589C80; 4[2-Formyl-3- Hydroxyphenoxymethyl] Benzoic Acid), A Potential Anti-Sickling Agent, Following Oral Administration To Healthy Subjects, 35(4), 419-425.
  • Rolan, P.E. (1996). The Exploratory Clinical Development of Tucaresol. M.D. dissertation, University of Adelaide, Australia, 1996. Retrieved from https://hdl.handle.net/2440/38411.
  • Service. R.F. (2022). Bad News for Paxlovid? Coronavirus Can Find Multiple Ways To Evade Covid-19 Drug. Science, June 29, 377(6602). doi:10.1126/science.add7726.
  • Shamsi, A., Mohammad, T., Anwar, S., AlAjmi, M.F., Hussain, A., Rehman, M.T., Islam, A., Hassan, M.I. (2020). Glecaprevir and Maraviroc are High-Affinity Inhibitors of SARS-CoV-2 Main Protease: Possible Implication in COVID-19 Therapy. Biosci. Rep., 40(6), BSR20201256. doi: 10.1042/BSR20201256.
  • Shen, Y., Ai, J., Lin, N., Zhang, H., Li, Y., Wang, H., Wang, S., Wang, Z., Li, T., Sun, F., et al. (2022). An Open Prospective Cohort Study of VV116 In Chinese Participants Infected with SARS-CoV-2 Omicron Variants. Emerg. Microbes Infect., 11(1), 1518-1523.
  • Trémolières, F. (2021).Antivirals in the Time of COVID-19 – Not As Easy As It Looks! Infect Dis Now, 51(1), 2- 6.
  • Vegivinti, C.T.R., Evanson, K.W., Lyons, H., Akosman, I., Barrett, A., Hardy, N., Kane, B., Keesari, P.R., Pulakurthi, Y.S., Sheffels, E., et al. (2022). Efficacy of Antiviral Therapies For COVID-19: A Systematic Review Of Randomized Controlled Trials. BMC Infect. Dis., 22(1), 107. doi:10.1186/s12879-022-07068-0.
  • Viera, J. Enanta. (2022). Pharmaceuticals Receives FDA Fast Track Designation For EDP-235, Its Oral 3CL Protease Inhibitor Specifically Designed For The Treatment and Prevention of COVID-19. Press Release. March 29, 2022.
  • Yang, T., Cuesta, A., Wan, X., Craven, G.B., Hirakawa, B., Khamphavong, P., May, J.R., Kath, J.C., Lapek, J.D. Jr., Niessen, S, et al. (2022). Reversible Lysine-Targeted Probes Reveal Residence Time-Based Kinase Selectivity. Nat Chem Biol., 18(9), 934-941.
  • Zhou, S., Hill, C.S., Sarkar, S., Tse, L.V., Woodburn, B.M.D., Schinazi, R.F., Sheahan, T.P., Baric, R.S., Heise, M.T., Swanstrom, R. (2021). -d-N4-Hydroxycytidine Inhibits SARS-Cov-2 Through Lethal Mutagenesis But Is Also Mutagenic To Mammalian Cells. J. Infect. Dis., 224(3), 415-419.
  • Christopher L. Penney, Boulos Zacharie and Jean-Simon Duceppe. (2023). Tucaresol: A Unique Oral Candidate Drug Ideally Accessible for Treatment of Covid-19 Disease. African Journal of Pharmaceutical Sciences, 3(1), 1-13. doi: 10.51483/AFJPS.3.1.2023.1-13.