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Abstract
Humic substances (HS) are complex natural mixtures comprising a large variety of compounds produced during decomposition of decaying biomass. The molecular composition of HS is extremely diverse as it was demonstrated with the use of high resolution mass spectrometry. The building blocks of HS are mostly represented by plant-derived biomolecules (lignins, lipids, tannins, carbohydrates, etc.). As a result, HS show a wide spectrum of biological activity. Despite that, HS remain a ‘biological activity black-box’ due to unknown structures of constituents responsible for the interaction with molecular targets. In this study, we investigated the antiviral activity of eight HS fractions isolated from peat and coal, as well as of two synthetic humic-like materials. We determined molecular compositions of the corresponding samples using ultra-high resolution Fourier-transform ion cyclotron resonance mass-spectrometry (FTICR MS). Inhibitory activity of HS was studied with respect to reproduction of tick-borne encephalitis virus (TBEV), which is a representative of Flavivirus genus, and to a panel of enteroviruses (EVs). The samples of natural HS inhibited TBEV reproduction already at a concentration of 1 µg/mL, but they did not inhibit reproduction of EVs. We found that the total relative intensity of FTICR MS formulae within elemental composition range commonly attributed to flavonoid-like structures is correlating with the activity of the samples. In order to surmise on possible active structural components of HS, we mined formulae within FTICR MS assignments in the ChEMBL database. Out of 6502 formulae within FTICR MS assignments, 3852 were found in ChEMBL. There were more than 71 thousand compounds related to these formulae in ChEMBL. To support chemical relevance of these compounds to natural HS we applied the previously developed approach of selective isotopic exchange coupled to FTICR MS to obtain structural information on the individual components of HS. This enabled to propose compounds from ChEMBL, which corroborated the labeling data. The obtained results provide the first insight onto the possible structures, which comprise antiviral components of HS and, respectively, can be used for further disclosure of antiviral activity mechanism of HS.
Highlights
Antiviral therapy presents a great challenge for drug discovery because the mutation rate of viruses is high and new pathogenic strains and species emerge quickly[1]
Antiviral activity of the ten Humic substances (HS) samples used in this study was assessed by plaque reduction test in Porcine embryo kidney (PEK) cells for tick-borne encephalitis virus (TBEV) and by cytopathic effect inhibition test in RD cells for a panel of enteroviruses
Neither samples show any inhibition of cytopathic effect caused by enteroviruses (EV EC50_pre, Table 1)
Summary
Antiviral therapy presents a great challenge for drug discovery because the mutation rate of viruses is high and new pathogenic strains and species emerge quickly[1]. Deeper structural study using fragmentation approaches is hampered by a lack of suitable preliminary separation techniques and extreme diversity of molecular compositions, which results in the increased amount of molecular formulae assignments after HS fractionation rather than in narrowing of complexity[27] This leaves the question open with regard to individual HS components responsible for the bioactivity of these complex mixtures. Data mining of mass-spectrometric results in chemical databases enables to avoid re-identification of well-known compounds, which is usually referred to a dereplication strategy[32] Application of such approaches is important for structural studies of biologically active metabolites, which are time-consuming, require high amounts of the parent materials and often lead to the unsatisfactory results. The objective of this study was to develop a chemoinformatic approach for the analysis of chemical space of bioactive HS components and exploration of possible structural motifs via a search for compounds matching FTICR MS-assigned molecular formulae in ChEMBL database. The obtained results provide first insight on the possible structures, which comprise antiviral components of HS and, respectively, can be used for further dissection of HS antiviral activity mechanism
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