An Update on the Bananins: Anti-RNA-Viral Agents with Unique Structural Signature

Andreas   J.   Kesel

doi:10.2174/22113626130102

Abstract

The purpose of this contribution is to introduce an update on the bananins or trioxa-adamantane-triols (TATs), a class of anti-RNA-(corona)viral agents which are active against human severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) and dengue virus type 2 (DENV-2). The prototype compound bananin (BN) inhibited replication of SARS-CoV through allosteric inhibition of SARS-CoV nsp13 ATPase/NTPase RNA/DNA helicase protein enzymatic function(s). The vanillinbananin (VANBA) blocked DENV-2 entry into host cells (Vero) by inhibiting endosome vacuole acidification, similar to concanamycin A. The structures of BN and VANBA were investigated by elemental analysis. It could be shown that both BN and VANBA matured after synthesis by poly-condensation of their 1,5,7-triol hydroxy groups, yielding brown to black colored powders. These high-polymer materials gave irregular NMR spectra, but re-constituted the monomeric TAT in aqueous media like cell culture and body fluids. Up to date eleven bananins [BN, IBNCA, ABNCA, ansaBN, euBN, VANBA, ethylVANBA, euVANBA, Ehrlich BN, [6]prismaneBN, nitrodiBN] were produced, four of which (BN, IBNCA, euBN, VANBA) inhibited both SARS-CoV replicase 1b protein nsp13 ATPase and DNA helicase enzymatic activity in vitro. The unique cage structure of the TATs was proved by NMR spectroscopy, IR spectroscopy, and UV/VIS spectrophotometry. Some modern two-dimensional NMR techniques (HH-COSY, gs-HMBC, gs-HSQC) and high resolution electrospray mass spectrometry (HR-ESI MS) were used to investigate the more complex bananins like [6]prismaneBN. The latter compound was reacted with all-trans-retinoic acid (ATRA) to yield the 12th TAT [6]prismaneBN-ATRA which served as tool for proving the general bananin structure(s) by HR-ESI MS. The group of TATs includes compounds with very unusual structures [ansaBN, [6]prismaneBN, nitrodiBN, [6]prismaneBN-ATRA], achieved only by skillful combination of organic synthetic achievements. The triazahexaprismane derivative [6]prismaneBN, and the dinitrohexaprismane derivative nitrodiBN, are the first successfully synthesized true hexaprismane [[6]prismane] derivatives. Because of theoretical considerations the bananins bear a great future intrinsic potential to inhibit RNA-viral replication of various RNA viruses, especially of hepatitis C virus (Flaviviridae), avian flu (influenza virus H5N1, Orthomyxoviridae), Ebola and Marburg virus (Filoviridae), Nipah and Hendra virus (Paramyxoviridae), Hantaan virus (Bunyaviridae), Lassa virus (Arenaviridae), yellow fever virus and dengue virus (Flaviviridae), tick-borne encephalitis virus (FSME virus, Flaviviridae), rabies virus (Rhabdoviridae), and, possibly, certain Picornaviridae (poliovirus, hepatitis A virus, coxsackievirus, echovirus, rhinovirus). Future work will be needed to define the true antiviral chemotherapeutic spectrum of the bananins which might in some way resemble the capacity of the first broad-spectrum virustatic drug ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide), but, as to be expected, without exhibiting the pronounced host cell toxicity of ribavirin.

Keywords: Antiviral agents, antiviral chemotherapy, bananin, dengue virus, SARS coronavirus, trioxa-adamantane-triol, viral entry, viral helicase.