Anti-Inflammatory, Antiallergic, and COVID-19 Main Protease (Mpro) Inhibitory Activities of Butenolides from a Marine-Derived Fungus Aspergillus terreus

Abstract

In December 2020, the U.K. authorities reported to the World Health Organization (WHO) that a new COVID-19 variant, considered to be a variant under investigation from December 2020 (VUI-202012/01), was identified through viral genomic sequencing. Although several other mutants were previously reported, VUI-202012/01 proved to be about 70% more transmissible. Hence, the usefulness and effectiveness of the newly U.S. Food and Drug Administration (FDA)-approved COVID-19 vaccines against these new variants are doubtfully questioned. As a result of these unexpected mutants from COVID-19 and due to lack of time, much research interest is directed toward assessing secondary metabolites as potential candidates for developing lead pharmaceuticals. In this study, a marine-derived fungus Aspergillus terreus was investigated, affording two butenolide derivatives, butyrolactones I (1) and III (2), a meroterpenoid, terretonin (3), and 4-hydroxy-3-(3-methylbut-2-enyl)benzaldehyde (4). Chemical structures were unambiguously determined based on mass spectrometry and extensive 1D/2D NMR analyses experiments. Compounds (1-4) were assessed for their in vitro anti-inflammatory, antiallergic, and in silico COVID-19 main protease (M^pro) and elastase inhibitory activities. Among the tested compounds, only 1 revealed significant activities comparable to or even more potent than respective standard drugs, which makes butyrolactone I (1) a potential lead entity for developing a new remedy to treat and/or control the currently devastating and deadly effects of COVID-19 pandemic and elastase-related inflammatory complications.

Keywords: Aspergillus terreus; COVID-19 Mpro; antiallergic; butenolides; elastase.

Figure 1

Chemical structures of 1–4.

Figure 2

In vitro elastase inhibitory activity of butyrolactone I (1) in the cell-free system. The results are presented as mean ± S.E.M. (n = 3). * p < 0.05, ** p < 0.01 compared with the control (0.1% DMSO).

Figure 3

Docking of compound butyrolactone I (1) (blue) in the active site of human NE. (a) Interactions of 1 with amino acids in the active site. (b) Docking pose of 1.

Figure 4

Poses and interactions of tested compounds in the active site of SARS-CoV-2 main protease (6LU7). (a) Interactions of butyrolactone III (2) (Cyan) in the active site. (b) Overlapping of butyrolactone III (2) with co-crystalized ligand N3 (yellow). (c) Interactions of terretonin (3) (pink) in the active site. (d) Overlapping of terretonin (3) with co-crystallized ligand N3 (yellow). (e) Binding pose of butyrolactone I (1). (f) Overlapping of the binding poses of butyrolactone I (1) and butyrolactone III (2). (g) Structure of the co-crystallized ligand (N3) in 6LU7 pdb file.