Discovery of lead natural products for developing pan-SARS-CoV-2 therapeutics

Persistent SARS-CoV-2 Infection, EBV, HHV-6 and Other Factors May Contribute to Inflammation and Autoimmunity in Long COVID

“…Pérez-Vargas et al sought to explore a novel spectrum of antivirals that would be effective against both existing and the seemingly endlessly evolving SARS-CoV-2 variants of concern (VOCs). They screened a library of natural products (NPs) obtained from plants, fungi, bacteria and marine sponges and achieved promising results, finding that NPs with highly diverse chemical structures have the potential for being developed into SARS-CoV-2 therapeutics [ 216 ].…”

Synthetic Analogs of the Sponge Sesterterpenoid Alotaketal C are Potent Inhibitors of SARS-CoV-2 Omicron BA.1 and BA.5 Infections of Human Lung Cells

“…collected in Howe Sound, British Columbia. 15 Alotaketal C (1) had an effective dose (EC 50 ) of 110 nM in the screening assay with a Calu-3 host cell cytotoxicity (CC 50 ) of 100 μM giving it a selectivity index of ∼900, and it showed single digit micromolar and 14 Alotaketal C (1) was initially discovered in our laboratory as part of a screen for HIV-1 latency reversal agents, and it was shown to be a protein kinase C (PKC) activator that is more potent than the reference standard PKC activator prostratin. 15 Prompted by this observation, we showed that the PKC activators prostratin and bryostatin were also inhibitors of SARS-CoV-2 growth in Calu-3 cells and that the PKC inhibitors Go6983 and Go6976 dramatically increased the SARS-CoV-2 infection in the Calu-3 cell assays.…”

“…Natural products are a rich source of novel bioactive chemical diversity that has historically played an important role in providing lead compounds for the development of new antibacterial, antiviral, and anticancer therapeutics. , As part of a program aimed at finding new antiviral natural product chemical scaffolds active against SARS-CoV-2, we screened a unique library of pure plant, microbial, and marine invertebrate natural products for their ability to inhibit the infection of SARS-CoV-2 in Calu-3 lung epithelial cells . Our high-content cell-based screening approach used an engineered viral strain mNG-SARS-CoV-2 that has an mNeonGreen fluorescent reporter and represents the parental variant.…”

“…Alotaketal C ( 1 ) was initially discovered in our laboratory as part of a screen for HIV-1 latency reversal agents, and it was shown to be a protein kinase C (PKC) activator that is more potent than the reference standard PKC activator prostratin . Prompted by this observation, we showed that the PKC activators prostratin and bryostatin were also inhibitors of SARS-CoV-2 growth in Calu-3 cells and that the PKC inhibitors Go6983 and Go6976 dramatically increased the SARS-CoV-2 infection in the Calu-3 cell assays . There are literature reports that PKC activity can lead to shedding of angiotensin converting enzyme 2 (ACE2) receptors from the surface of cells. , This led to our hypothesis that alotaketal C ( 1 ) is acting as a host-directed anti-SARS-CoV-2 agent by stimulating cell surface shedding of the ACE2 receptors that are the entry point of the SARS-CoV-2 virus into human cells .…”

“…collected in Howe Sound, British Columbia . Alotaketal C ( 1 ) had an effective dose (EC 50 ) of 110 nM in the screening assay with a Calu-3 host cell cytotoxicity (CC 50 ) of 100 μM giving it a selectivity index of ∼900, and it showed single digit micromolar and submicromolar EC 50 s against SARS-CoV2 Delta (4.9 μM), Omicron BA.1 (700 nM), Omicron BA.2 (700 nM), and Omicron BA.5 (300 nM) VOCs grown in Calu-3 cells indicating promising Pan-SARS-CoV-2 efficacy …”