A system of protein target sequences for anti-RNA-viral chemotherapy by a vitamin B6-Derived zinc-Chelating trioxa-adamantane-triol

Abstract

The synthesis of the structurally unusual heterotricyclic compound 1-[3-hydroxy-5-(hydroxymethyl)-2-methyl-4-pyridinyl]-2,8,9-trioxaadamantane-3,5,7-triol (trivially named bananin, BN) from pyridoxylidenephloroglucinol and a theoretical prospect on possible biological activities of BN are presented in this report. Pyridoxylidenephloroglucinol is synthesized by Knoevenagel condensation of the vitamin B6 aldehyde pyridoxal with phloroglucinol. Pyridoxylidenephloroglucinol rearranges to light-yellow (4'RS)-1',4'-dihydrobananin by refluxing in 5M hydrochloric acid. Air oxidation subsequently forms BN in the heat which immediately yields orange-yellow (4'RS)-4'-chloro-1',4'-dihydrobananin by 1,4-addition of hydrogen chloride. This intermediate could be isolated but, interestingly, not a BN hydrochloride. Brown BN is finally achieved by base-catalyzed elimination of hydrogen chloride from (4'RS)-4'-chloro-1',4'-dihydrobananin. Regarding possible biological activities, it was demonstrated that BN acts as zinc (Zn2+) chelator. Therefore, a target of interest could be the human immunodeficiency virus type 1 (HIV-1) zinc finger HIV-1 RNA-binding nucleocapsid protein p7 (NCp7). Through suggested zinc ejection from HIV-1 genomic RNA psi-element-binding and HIV-1-RNA-duplex packaging NCp7 by BN, thus rendering NCp7 functionally obsolete, it is deduced that HIV-1 replication and effective infectious virion encapsidation could be inhibited by BN. Furthermore, theoretical and structural considerations propose that BN is converted into bananin 5'-monophosphate (BNP) by the cell type-ubiquitous human enzyme pyridoxal kinase (EC 2.7.1.35). Together with the putative antilentiviral retinoid vitamin A-vitamin B6 conjugate analogue B6RA (Kesel, A. J. Biochem. Biophys. Res. Comm. 2003, 300, 793), BNP is postulated to serve as effector in a system of protein target sequences RX(D/E) of RNA virus components. Human immunodeficiency Retroviridae (HIVs) could possibly be influenced by B6RA and BNP. In addition, candidate targets of B6RA and BNP could be adsorption, transcription and/or viral RNA replication of an interestingly wide RNA virus selection including Picornaviridae (poliovirus, human coxsackievirus, hepatitis A virus), Flaviviridae (yellow fever virus, Dengue virus, West Nile virus, Kunjin virus, St. Louis encephalitis virus, hepatitis C virus), Togaviridae (rubella virus), Coronaviridae (human coronavirus, human SARS-associated coronavirus), Rhabdoviridae (rabies virus), Paramyxoviridae (human parainfluenza virus, measles virus, human respiratory syncytial virus), Filoviridae (Marburg virus, Ebola virus), Bornaviridae (Borna disease virus), Bunyaviridae (Hantaan virus), Arenaviridae (Lassa virus), and Reoviridae (human rotavirus). The postulated scope of 'metabolically trapped' BNP might resemble the antiviral spectrum of the RNA-viral virustatic ribavirin.

Associations between immune-suppressive and stimulating drugs and novel COVID-19—a systematic review of current evidence

“…A separate Chinese study, which separated SARS-CoV patients into 4 treatment groups, identified early high-dose steroids in combination with a quinolone as producing the best patient outcomes [19]. Nevertheless, one review stated that the WHO does not currently recommend corticosteroids in other viral diseases such as Dengue as the 'glucocorticoid-mediated stimulation of the hypothalamic-pituitaryadrenal axis can also drive lymphocytopenia, or it may promote exaggerated pro-inflammatory responses that eventually cause a worsening of the pathogenic condition' [20].…”

“…• ADAM-17 regulates IL-6 class switching as a mediator between pro-and anti-inflammatory responses to viral antigenic stimuli in Ebola, SARS-CoV and dengue infections in humans. Therefore, ADAM-17 should be considered as a potential target molecule for novel antiviral drug discovery for infections, such as SARS-CoV [20] • SARS-CoV ssRNA is a new therapeutic target given its capacity to cause acute lung injury in mice with a high mortality rate in vivo experiment suggesting that SARS-CoV specific GU-rich ssRNA plays a very important role in the cytokine storm associated with a dysregulation of the innate immunity [40]. • DUSP1 and p38 MAPK are potential therapeutic targets for coronavirus infectious bronchitis virus, given their capability to reduce the production of an excessive amount of IL-6 and IL-8 in the infected cells [41].…”

Anti‐influenza virus agents: Synthesis and mode of action

“…The bananins were synthesized by the reaction of phloroglucinol (most likely in its triketo tautomeric form) with aromatic aldehydes, catalyzed by hydrochloric acid or sodium hydroxide in aqueous solution. 57 Generally, acidic catalysis was used due to the degradation of pyridoxal under highly basic conditions. Alkaline catalysis was used for reaction with aromatic aldehydes such as vanillin to obtain Vanillinbananin (VBN) 55.…”

Interaction of viral proteins with metal ions: role in maintaining the structure and functions of viruses

“…The structurally unusual heterotricyclic compound named bananin (BN) has several roles including Zn 2+ chelator, and a target of interest is HIV-1 ZF, HIV-1 RNA-binding NC7. In addition, the targets of BN could be adsorption, transcription and/ or viral RNA replication of a interestingly wide range RNA viruses reviewed in [11]. The findings summarized in Table 2 show that various viral proteins can bind different metal ions.…”