Discovery of lead natural products for developing pan-SARS-CoV-2 therapeutics, 2022, Perez-Vargas, Shapira

2022 Dec 8;209:105484.
doi: 10.1016/j.antiviral.2022.105484. Online ahead of print.

Discovery of lead natural products for developing pan-SARS-CoV-2 therapeutics
Jimena Pérez-Vargas 1, Tirosh Shapira 1, François Jean 21 et al
Affiliations

• PMID: 36503013
  
• PMCID: PMC9729583
  
• DOI: 10.1016/j.antiviral.2022.105484

Free PMC article
Abstract
The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a global public health crisis. The reduced efficacy of therapeutic monoclonal antibodies against emerging SARS-CoV-2 variants of concern (VOCs), such as omicron BA.5 subvariants, has underlined the need to explore a novel spectrum of antivirals that are effective against existing and evolving SARS-CoV-2 VOCs. To address the need for novel therapeutic options, we applied cell-based high-content screening to a library of natural products (NPs) obtained from plants, fungi, bacteria, and marine sponges, which represent a considerable diversity of chemical scaffolds. The antiviral effect of 373 NPs was evaluated using the mNeonGreen (mNG) reporter SARS-CoV-2 virus in a lung epithelial cell line (Calu-3). The screening identified 26 NPs with half-maximal effective concentrations (EC50) below 50 μM against mNG-SARS-CoV-2; 16 of these had EC50 values below 10 μM and three NPs (holyrine A, alotaketal C, and bafilomycin D) had EC50 values in the nanomolar range. We demonstrated the pan-SARS-CoV-2 activity of these three lead antivirals against SARS-CoV-2 highly transmissible Omicron subvariants (BA.5, BA.2 and BA.1) and highly pathogenic Delta VOCs in human Calu-3 lung cells. Notably, holyrine A, alotaketal C, and bafilomycin D, are potent nanomolar inhibitors of SARS-CoV-2 Omicron subvariants BA.5 and BA.2. The pan-SARS-CoV-2 activity of alotaketal C [protein kinase C (PKC) activator] and bafilomycin D (V-ATPase inhibitor) suggest that these two NPs are acting as host-directed antivirals (HDAs). Future research should explore whether PKC regulation impacts human susceptibility to and the severity of SARS-CoV-2 infection, and it should confirm the important role of human V-ATPase in the VOC lifecycle. Interestingly, we observed a synergistic action of bafilomycin D and N-0385 (a highly potent inhibitor of human TMPRSS2 protease) against Omicron subvariant BA.2 in human Calu-3 lung cells, which suggests that these two highly potent HDAs are targeting two different mechanisms of SARS-CoV-2 entry. Overall, our study provides insight into the potential of NPs with highly diverse chemical structures as valuable inspirational starting points for developing pan-SARS-CoV-2 therapeutics and for unravelling potential host factors and pathways regulating SARS-CoV-2 VOC infection including emerging omicron BA.5 subvariants.



Link to abstract also included in UBC article below:

B.C. sea sponge has COVID-blocking powers
https://news.ubc.ca/2023/01/09/b-c-sea-sponge-has-covid-blocking-powers/

ETA: edited authors' list

 

Probably should not try to read when I am tired, but first I could not get beyond the title. I assume it is ‘lead’ as in front runner rather than ‘lead’ the metal.

Once I did go onto the abstract I kept having to check it was in English. Even began to wonder if I was having a stroke, but fortunately no other signs: visual fields seem intact, face remains symmetrical and no right sided hemiparesis (as presumably a stroke taking out reading comprehension would be left brain).

 

Biochemists - spending all day in a hazmat suit messes up their communication skills.

Full paper: https://www.sciencedirect.com/science/article/pii/S0166354222002534?via=ihub

"2.3. Natural products

Our natural product screening library contains 373 pure natural products representing a large diversity of chemical scaffolds isolated from a broad spectrum of plants, invertebrates, or microorganisms collected in diverse terrestrial and marine habitats (Table S1). Terrestrial plants and microorganisms were collected in Thailand, Brazil, Canada, and Sri Lanka. Marine invertebrates and microorganisms were collected in ocean waters off the coasts of Canada, Brazil, Italy, Papua New Guinea, Indonesia, Dominica, and Sri Lanka.

Most NPs in the screening library were discovered and first reported in the literature by the co-authors. Some of the pure natural products isolated by the coauthors had been previously reported in the literature by other research groups. The structures of all the NPs discovered by the coauthors were elucidated by a detailed analysis of nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS), and/or single-crystal X-ray diffraction data. The chemical structure and purity of our three lead NPs (Holyrine A, alotaketal C, and bafilomycin D) was confirmed by NMR analyses (Fig. S1). Literature references detailing the discovery of the lead 26 active compounds are provided.

5. Conclusion

In summary, we applied a cell-based fluorescent-screening assay to identify promising anti-SARS-CoV-2 compounds from a diverse NP library. Three lead compounds (holyrine A, alotaketal C, and bafilomycin D) demonstrated nanomolar antiviral potency against mNG-SARS-CoV-2, and we confirmed they had low micromolar to nanomolar pan-SARS-CoV-2 antiviral activity against four VOCs (Delta, Omicron BA.1, BA.2 and BA.5). Further studies may be required to determine the broad-spectrum antiviral activity of the additional 47 NPs not investigated here that demonstrated >50% inhibition at 50 μM using the mNG-SARS-CoV-2, with <20% cell loss. Due to the unique biology of SARS-CoV-2 VOCs in terms of their transmission and pathogenesis, a number of these NPs may present additional promising leads.

Overall, our study provides insight into the potential of NPs with highly diverse chemical structures as valuable inspirational starting points for developing pan-SARS-CoV-2 therapeutics. These therapeutics could be used as part of multidrug regimens to counteract the increasing antiviral drug resistance to the currently limited repertoire of monotherapies against SARS-CoV-2 infections (Li et al., 2022; Schultz et al., 2022; Szemiel et al., 2021). In addition, our antiviral NPs provide new patent-free academia-originated leads for further development as alternatives to patent-protected pharmaceuticals."

 

@Peter Trewhitt

Should I laugh? Well I did at what you said.

The title is a little difficult as the word "lead" usually means the metal, at least to me.

But that was indeed the study title as you have ascertained.

This was a University of British Columbia study.

Hope you're feeling better....

 

Thanks @CRG for the full article.

 

Yes my post was tongue in cheek, though I did have a brief panic when I first realised I was staring at a string of words that were presumably in my native language but made no sense.

 

Thanks Peter.

I think like many with ME, I find long paragraphs with dense info causes data overload.

Not sure if you noted this for yourself, but I know some complex info pwME come across can be difficult to absorb.

And, the double or multiple meanings for words can cause stumbling blocks for some pwME.

 

Yes, yes and yes, but also I struggle with acronyms and abbreviations.

 

Absolutely, me too.

 

As an ex TEFL teacher I would guess this is non idiomatic English, enthusiastically composed by non native speakers.

Agree it reads in a confusing manner, glad I am not the only one.

"Lead" in the title should at least be "leading" to avoid ambiguity with Pb also "scaffold" instead of molecular structure is non idiomatic usage and a slight malapropism as scaffold is usually used to imply support to other structures e.g microtubules or histones which is not the meaning here.

Kind of strange but it highlights how large a role idiom and convention play in linguistic communication especially in scientific fields.

I suppose you have to give them credit for trying but also one would wish they had a native English speaker with bioscience experience who could proof read it for them!

Nevertheless it sounds like they put a lot of work into it and depending on replicability, may have discovered some potentially useful antiviral compounds. For which I suppose we should be grateful as opposed to complacently bombastic!

 

Hi @boolybooly

Agreed, I debated just using the University's article about the research, and not the research article itself, as for one, the title, including the word "lead" is confusing. And, agreed the researchers have put a lot of work into this study.


I added the University's, more readable PR article in my first post; I have also included it here:

https://news.ubc.ca/2023/01/09/b-c-sea-sponge-has-covid-blocking-powers/

 

The PR article is easier to read.

If I was responsible for rewording the title I would change it from,
"Discovery of lead natural products for developing pan-SARS-CoV-2 therapeutics"
to
"Discovery of biogenic antiviral candidates against SARS-CoV-2."


These discoveries look like they could be potential life savers but there is a lot more work required to verify that. Using the word lead in that way seems rather promotional as if it was advertising copy and one wonders whether there is an element of hyperbole involved. In particular I wonder how toxic such molecules might be in vivo if they are such good infection blockers.


As an aside, because of this hope for therapy, these molecules and their sources might also prove to be a good example demonstrating why the current ongoing anthropogenic mass extinction impoverishes us all and our descendants for all eternity since if species go extinct they cannot furnish molecules of this kind and there is currently no way to predict which molecules from what species will be able to help with whatever near term future health crises humanity may encounter. In centuries to come computer modelling might take over but for now the next "penicillin" is likely to be found by this kind of investigation of the living species of Earth's ecosystem.

I wrote a little bloglet about this using the perspective of futurology but medicine is a good shorter term reason we should give conservation a high priority.
https://boolosophy.blogspot.com/2020/08/the-priceless-value-of-life-for-future.html

 

Excellent points! Thanks!