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COVID-19 is a respiratory disease caused by SARS-CoV-2, an enveloped positive sense RNA virus. The SARS-CoV-2 spike glycoprotein, human angiotensin-converting enzyme 2 (ACE2) and human transmembrane protease serine 2 (TMPRSS2) are essential for the host cell-mediated viral entry. Targeting these proteins represent viable options to stop the first stage of infection and transmission. Hence, 97 alkaloids from African medicinal plants with reported antiviral activity were evaluated for this purpose via in silico studies. These alkaloids were docked for their interactions with SARS-CoV-2 spike glycoprotein, ACE2, and TMPRSS2. Top 20 alkaloids with highest binding affinities were further screened for their interactions with spike glycoprotein of SARS-CoV and MERS-CoV, and with ACE2-SARS-CoV-2 receptor-binding domain complex (ACE2-RBD). The energy profiling, molecular dynamics simulation (MDS), binding free energy base on Molecular Mechanics/Generalized Born Surface Area (MMGBSA), clustering of MDS trajectories, and virtual physicochemical and pharmacokinetic screening of the best docked alkaloids were performed. Results revealed that more than 15 alkaloids interacted better than the reference compounds. 10–Hydroxyusambarensine and Cryptospirolepine were docked in a similar binding pattern to the S1-specificy pocket of TMPRSS2 as camostat (reference inhibitor). The strong binding affinities, stability of the alkaloid-protein complexes and amino acid interactions displayed by cryptospirolepine, 10-hydroxyusambarensine, and cryptoquindoline with important binding hotspots of the proteins suggest these alkaloids have the potential of altering the capacity of SARS-CoV-2 membrane mediated host cell entry. Further in vitro and in vivo evaluation of these “drug-like” alkaloids as potential inhibitors of coronavirus cell entry is proposed. Communicated by Ramaswamy H. Sarma

The anti-proliferative activity of dietary flavonoid fisetin has been validated in various cancer models. Establishing its precise mechanism of action has proved somewhat challenging given the multiplicity of its targets. We demonstrated that YB-1 promotes epithelial-to-mesenchymal transition and its inhibition suppressed tumor cell proliferation and invasion. The p90 ribosomal S6 kinase (RSK), an important ERK effector, activates YB-1 to drive melanoma growth. We found that fisetin treatment of monolayer/3-D melanoma cultures resulted in YB-1 dephosphorylation and reduced transcript levels. In parallel, fisetin suppressed mesenchymal markers and matrix-metalloproteinases in melanoma cells. Data from cell-free/cell-based systems indicated that fisetin inhibited RSK activity through binding to the kinase. Affinity studies for RSK isoforms evaluated stronger interaction for RSK2 than RSK1. Competition assays performed to monitor binding responses revealed that YB-1 and RSK2 do not compete, rather binding of fisetin to RSK2 promotes its binding to YB-1. Fisetin suppressed YB-1/RSK signaling independent of its effect on ERK, and reduced MDR1 levels. Comparable efficacy of fisetin and vemurafenib for inhibiting melanoma growth was noted albeit through divergent modulation of ERK. Our studies provide insight into additional modes of regulation through which fisetin interferes with melanoma growth underscoring its potential therapeutic efficacy in disease progression.

Corona Virus Disease 2019 (COVID-19) is a pandemic caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Exploiting the potentials of phytocompounds is an integral component of the international response to this pandemic. In this study, a virtual screening through molecular docking analysis was used to screen a total of 226 bioactive compounds from African herbs and medicinal plants for direct interactions with SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). From these, 36 phytocompounds with binding affinities higher than the approved reference drugs (remdesivir and sobosivir), were further docked targeting the active sites of SARS-CoV-2, as well as SARS-CoV and HCV RdRp. A hit list of 7 compounds alongside two positive controls (remdesivir and sofosbuvir) and two negative controls (cinnamaldehyde and Thymoquinone) were further docked into the active site of 8 different conformations of SARS-CoV-2 RdRp gotten from molecular dynamics simulation (MDS) system equilibration. The top docked compounds were further subjected to predictive druglikeness and ADME/tox filtering analyses. Drugable alkaloids (10’–hydroxyusambarensine, cryptospirolepine, strychnopentamine) and flavonoids (usararotenoid A, and 12α-epi-millettosin), were reported to exhibit strong affinity binding and interactions with key amino acid residues in the catalytic site, the divalent-cation–binding site, and the NTP entry channel in the active region of the RdRp enzyme as the positive controls. These phytochemicals, in addition to other promising antivirals such as remdesivir and sofosbuvir, may be exploited towards the development of a cocktail of anti-coronavirus treatments in COVID-19. Experimental studies are recommended to validate these study.

Background The herbal preparation DAS-77, used for the treatment of various ailments in Nigeria, contains the milled bark of Mangifera indica L. and root of Carica papaya L. Toxicological assessment of the preparation was carried out in this study. Methods In the acute toxicity study, DAS-77 was administered to mice p.o. up to 20 g/kg in divided doses and i.p. at 250–3000 mg/kg. Mortality within 24 h was recorded. In the chronic toxicity study, rats were treated p.o. for 90 days at doses of 80, 400 (therapeutic dose, TD) and 2000 mg/kg. By 90 days, animals were sacrificed and blood samples collected for hematological and biochemical analysis. Organs were harvested for weight determination, antioxidants and histopathological assessments. Results DAS-77 did not produce any lethality administered p.o. up to 20 g/kg in divided doses but the i.p. LD50 was 1122.0 mg/kg. At TD, DAS-77 produced significant (p < 0.05) reductions in body weight, food intake and K+, and increases in ovary weight, neutrophils and HDL, which were reversible. Histopathological presentations were generally normal. Effects at the other doses were comparable to those at TD except for reversible increases in antioxidants in the liver, kidney and testes, and sperm abnormality, and reductions in liver enzymes, sperm motility and count. Conclusions Findings in this study revealed that DAS-77 is relatively safe with the potential for enhancing in vivo antioxidant activity. However, possibly reversible side-effects include electrolyte imbalance and sterility in males.