Tuaimenal A, a Meroterpene from the Irish Deep-Sea Soft Coral Duva florida, Displays Inhibition of the SARS-CoV-2 3CLpro Enzyme

Abstract

Cold water benthic environments are a prolific source of structurally diverse molecules with a range of bioactivities against human disease. Specimens of a previously chemically unexplored soft coral, Duva florida , were collected during a deep-sea cruise that sampled marine invertebrates along the Irish continental margin in 2018. Tuaimenal A ( 1 ), a cyclized merosesquiterpenoid representing a new carbon scaffold with a highly substituted chromene core, was discovered through exploration of the soft coral secondary metabolome via NMR-guided fractionation. The absolute configuration was determined through vibrational circular dichroism. Functional biochemical assays and in silico docking experiments found tuaimenal A selectively inhibits the viral main protease (3CLpro) of SARS-CoV-2.

Enzyme Inhibitors from Gorgonians and Soft Corals

“…Inhibitors of this protease have proved to be effective in the inhibition of viral replication in cell-based assays [ 68 ]. An inhibitor of the SARS-CoV-2 3CLpro protease, described as a cyclized merosesquiterpenoid with a new carbon scaffold and composed by a highly substituted chromene core, was found in Duva florida ( Table 3 and Figure 3 ) [ 61 ]. This compound, named Tuaimenal A ( 44 ), showed no inhibitory activity against other cysteine proteases ( Fasciola hepatica cathepsin L1 and L3, and human cathepsin L) or serine proteases (trypsin, chymotrypsin, and thrombin), suggesting a particular specificity towards 3CLpro protease.…”

Tuaimenals B–H, Merosesquiterpenes from the Irish Deep-Sea Soft Coral Duva florida with Bioactivity against Cervical Cancer Cell Lines

“…A molecular formula of C 23 H 30 O 4 for 10 was confirmed from HRESIMS ([M – H] − : m / z 369.2089, calcd 369.2071), corroborated by 1 H and 13 C NMR spectra. Interestingly, 10 was previously assigned by Avalon et al (2022) as existing in the R configuration about the C-9 stereocenter on the basis of comparisons of experimental vibrational circular dichroism (VCD) data to computationally predicted values for each enantiomer . While significant overlap between experimental data and in silico predictions did exist indicating this assignment of absolute configuration, the observed VCD and optical rotation (OR) signals were both inconsistently low, incongruent with an enantiomerically pure metabolite.…”

“… 9 Justification for this unique substitution pattern about the chromene core was posed by Avalon et al as resulting from a divergence from the typical tocopherol biosynthetic pathway at the homogentisate phytyltransferase step. 10 Further, tuaimenal A showed promising potential in inhibiting the main protease of SARS-CoV-2 in silico as well as weak activity as a cytotoxic agent against cervical cancer. 10 Herein we report further tandem mass spectrometry (MS/MS) and nuclear magnetic resonance (NMR) guided investigation into analogous metabolites resulting in the isolation, characterization, and cytotoxic evaluation of seven additional tuaimenals, B–H ( 1 – 7 ), two known A-ring-aromatized steroids ( 8 , 9 ), and tuaimenal A ( 10 ).…”

“…Interestingly, 10 was previously assigned by Avalon et al (2022) as existing in the R configuration about the C-9 stereocenter on the basis of comparisons of experimental vibrational circular dichroism (VCD) data to computationally predicted values for each enantiomer. 10 While significant overlap between experimental data and in silico predictions did exist indicating this assignment of absolute configuration, the observed VCD and optical rotation (OR) signals were both inconsistently low, incongruent with an enantiomerically pure metabolite. To determine if this trait was maintained for compounds 1 – 7 , optical rotation data were recorded at the maximal concentrations for measurement for each compound using a 50 μL cell, with the results displayed in Table 3 .…”

“…A merosesquiterpene with a highly substituted chromene core, 10 bears structural similarities to numerous terrestrial and marine secondary metabolites containing a “tocopherol-esque” backbone, perhaps most notably comparable to the two formylated tocotrienols 5-formyl-δ-tocotrienol and 7-formyl-δ-tocotrienol isolated from the stem bark of Garcinia virgata , with all three compounds possessing a benzaldehyde moiety . Justification for this unique substitution pattern about the chromene core was posed by Avalon et al as resulting from a divergence from the typical tocopherol biosynthetic pathway at the homogentisate phytyltransferase step . Further, tuaimenal A showed promising potential in inhibiting the main protease of SARS-CoV-2 in silico as well as weak activity as a cytotoxic agent against cervical cancer .…”