The LABEXTRACT plant extract bank, featuring diverse members of the Myrtaceae family from Brazilian hot spot regions, provides a promising avenue for bioprospection. Given the pivotal roles of the Spike protein and 3CL^pro and PL^pro proteases in SARS-CoV-2 infection, this study delves into the correlations between the Myrtaceae species from the Atlantic Forest and these targets, as well as an antiviral activity through both in vitro and in silico analyses. The results uncovered notable inhibitory effects, with Eugenia prasina and E. mosenii standing out, while E. mosenii proved to be multitarget, presenting inhibition values above 72% in the three targets analyzed. All extracts inhibited viral replication in Calu-3 cells (EC₅₀ was lower than 8.3 µg·mL⁻¹). Chemometric analyses, through LC-MS/MS, encompassing prediction models and molecular networking, identified potential active compounds, such as myrtucommulones, described in the literature for their antiviral activity. Docking analyses showed that one undescribed myrtucommulone (m/z 841 [M − H]⁻) had a higher fitness score when interacting with the targets of this study, including ACE2, Spike, PL^pro and 3CL^pro of SARS-CoV-2. Also, the study concludes that Myrtaceae extracts, particularly from E. mosenii and E. prasina, exhibit promising inhibitory effects against crucial stages in SARS-CoV-2 infection. Compounds like myrtucommulones emerge as potential anti-SARS-CoV-2 agents, warranting further exploration.

Scientists and researchers have been searching for drugs targeting the main protease (Mpro) of SARS-CoV-2, which is crucial for virus replication. This study employed a virtual screening based on molecular docking to identify benzoylguanidines from an in-house chemical library that can inhibit Mpro on the active site and three allosteric sites. Molecular docking was performed on the LaSMMed Chemical Library using 88 benzoylguanidine compounds. Based on their RMSD values and conserved pose, three potential inhibitors (BZG1, BZG2, and BZG3) were selected. These results indicate that BZG1 and BZG3 may bind to the active site, while BZG2 may bind to allosteric sites. Molecular dynamics data suggest that BZG2 selectively targets allosteric site 3. In vitro tests were performed to measure the proteolytic activity of rMpro. The tests showed that BZG2 has uncompetitive inhibitory activity, with an IC₅₀ value of 77 µM. These findings suggest that benzoylguanidines possess potential as Mpro inhibitors and pave the way towards combating SARS-Cov-2 effectively.

Background/Objectives: Since the emergence of the COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the discovery of compounds with antiviral potential from medicinal plants has been extensively researched. This study aimed to investigate plant metabolites with in vitro inhibitory potential against SARS-CoV-2 targets, including 3CL_pro, PL_pro, Spike protein, and RdRp. Methods: A systematic review was conducted following PRISMA guidelines, with literature searches performed in six electronic databases (Scielo, ScienceDirect, Scopus, Springer, Web of Science, and PubMed) from January 2020 to February 2024. Computational analyses using SwissADME, pkCSM, ADMETlab, ProTox3, Toxtree, and DataWarrior were performed to predict the absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles as well as other medicinal chemistry parameters of these compounds. Results: A total of 330 plant-derived compounds with inhibitory activities against the proposed targets were identified, with compounds showing IC₅₀ values as low as 0.01 μM. Our findings suggest that several plant metabolites exhibit significant in vitro inhibition of SARS-CoV-2 targets; however, few molecules exhibit drug development viability without further adjustments. Additionally, after these evaluations, two phenolic acids, salvianic acid A and protocatechuic acid methyl ester, stood out for their potential as candidates for developing antiviral therapies, with IC₅₀ values of 2.15 μM against 3CL_pro and 3.76 μM against PL_pro; respectively; and satisfactory in silico drug-likeness and ADMET profiles. Conclusions: These results reinforce the importance of plant metabolites as potential targets for antiviral drug discovery.

Endemic and pandemic viruses represent significant public health challenges, leading to substantial morbidity and mortality over time. The COVID-19 pandemic has underscored the urgent need for the development and discovery of new, potent antiviral agents. In this study, we present the synthesis and anti-SARS-CoV-2 activity of a series of benzocarbazoledinones, assessed using cell-based screening assays. Our results indicate that four compounds (4a, 4b, 4d, and 4i) exhibit EC50 values below 4 μM without cytotoxic effects in Calu-3 cells. Mechanistic investigations focused on the inhibition of the SARS-CoV-2 main protease (Mpro) and papain-like protease (PLpro) have used enzymatic assays. Notably, compounds 4a and 4b showed Mpro inhibition activity with IC50 values of 0.11 ± 0.05 and 0.37 ± 0.05 µM, respectively. Furthermore, in silico molecular docking, physicochemical, and pharmacokinetic studies were conducted to validate the mechanism and assess bioavailability. Compound 4a was selected for preliminary drug-likeness analysis and in vivo pharmacokinetics investigations, which yielded promising results and corroborated the in vitro and in silico findings, reinforcing its potential as an anti-SARS-CoV-2 lead compound.

We investigated statin-based peptidomimetic compounds as inhibitors of SARS-CoV-2 papain-like protease (PLpro) by in silico methods, including molecular docking/dynamic simulations and ADMET prediction, as well as enzymatic in vitro assays. Five compounds (LQMed 426, 428, 430, 431, and 432) were identified as having promising interactions with the active site and an allosteric site of PLpro. The docking poses in the active site revealed that the compounds interacted with the catalytic triad (Cys111, His272, and Asp286). Compound 426 stood out for forming significant hydrophobic interactions and hydrogen bonds. In molecular dynamic (MD) simulations, there was a tendency for the compounds to migrate to a pocket in the ubiquitin-like (Ubl) domain region, indicating possible allosteric inhibition. Principal component analysis (PCA) and free energy landscape (FEL) plot showed significant differences in the conformational stability of protein-ligand complexes. Complex 432 had the highest stability (PC1: 24.9%, PC2: 10.5%) with restricted movements, while complex 430 had the lowest stability and the highest PC1, indicating broader movements. Complexes 426 and 428 had intermediate stability. FEL analysis confirmed that complex 432 had multiple minimum energy clusters, suggesting a greater likelihood of stable enzyme-ligand complex. In vitro assays demonstrated that all compounds inhibited PLpro activity by at least 50%, with IC₅₀ values ranging from 0.85 µM to 4.06 µM. Compounds 426 and 432 were the most promising, with IC₅₀ of 0.85 µM and 1.46 µM, respectively, values comparable to the GRL-0617 reference inhibitor. Binding free energy analysis indicated that compounds 430 and 431 showed significant affinity for the allosteric site (-27 kcal/mol and − 14 kcal/mol, respectively), while compound 428 showed reduced stability. In addition, in silico pharmacokinetics and toxicity (ADMET) prediction revealed that statine-based compounds are promising compared to GRL-0617 due to the low potential of inhibition of CYP’s family and toxicity risk. Overall, the tested compounds, especially 426 and 432, showed potential as inhibitors of SARS-CoV-2 PLpro and may act by non-competitive or mixed mechanisms, making them promising candidates for developing antivirals against CoViD-19.

The Jurubatiba Sandbank National Park (PARNA Jurubatiba) is an ecological reserve characterized by harsh environmental conditions, including low rainfall, high sun exposure, and sandy soil. Among its native vegetation, Eremanthus crotonoides stands out for its richness in flavonoids, phenolic compounds, and sesquiterpene lactones. The objective of this study was to isolate and quantify sesquiterpene lactones from this species using ¹H NMR and to investigate their anti-SARS-CoV-2 potential and cytotoxicity against cancer cells. UPLC-(ESI)-MS/MS analyses enabled metabolite annotation, and semi-preparative HPLC-DAD allowed the isolation of centratherin and goyazensolide, which were identified by 1D and 2D NMR. In vitro assays showed that centratherin at 10 µM concentration reduced the viability of PC-3 and HCT-116 cancer cells by 100%, while goyazensolide had no noteworthy effects. Furthermore, enzymatic inhibition assays on SARS-CoV2 targets revealed that centratherin exhibited a lower apparent IC₅₀ of 12 µM against PL^pro, while goyazensolide was more active against 3CL^pro, with an IC₅₀ of 71 µM. Notably, the dichloromethane fraction demonstrated promising activity against both enzymes, with IC₅₀ values of 30 µM for PL^pro and 11 µM for 3CL^pro. This study reports, for the first time, the isolation of goyazensolide from E. crotonoides and highlights the potential of both sesquiterpene lactones as SARS-CoV-2 enzyme inhibitors. In contrast to centratherin, goyazensolide fortunately had almost no cytotoxic effects at inhibition concentration on the cells tested. This shows that anticancer and anti-SARS effects can be separated and should have different SARs, an important prerequisite for further development.