Over the last eight or so months there have been a series of papers, some short, some long, covering what can be considered as four major topics: natural products, repurposing of approved drugs, use of old vaccines as potential methods of alleviating the effects of CoV-2, and an idea of what needs to be done in the future.
On the basic natural product “front,” a very recent review by the Gerwick lab1 is an excellent discussion as to the potential of a large variety of natural products from all NP sources to be drug leads against a variety of RNA virus “types.” This is a paper that should be read as it covers a multitude of potential “entry points” into these viruses and points to a number of natural-product “classes” and their derivatives that could be potential leads, depending upon which viral pathogen(s) you wish to target.
Moving to looking at specific “targets” for natural products and their derivatives, scientists from Ulm and Essen Universities published a very interesting paper on peptide-based inhibitors of SARS-CoV-2 entry processes and also link back to SARS-CoV-1. These can include targets such as ACE-2, or proteases that activate proteases such as furin, transmembrane serine protease 2 (TMPRSS2) and cathepsin L.2 Interestingly, griffithsin was not listed in this paper, nor in the Christy1 paper, even though it was originally shown to inhibit coronaviruses. It should also be noted that back in 2007, a group from Brazil and Canada3 identified a marine-sourced coronavirus protease inhibitor as esculetin-4 carboxylic acid methyl ester (1); the base carboxylic acid had not been identified as a natural product prior to this report.
Another very recent paper4 from the same Mexican group referred to below gave more information on potential natural product structures that may uncover potential inhibitors of the SARS-CoV-2 main protease. They give some of the basic structures that are in their better hits, including molecules such as the angiotensin derivatives that would be expected from the binding characteristics of CoV-2. A lot more information is in their supplementary information which can be obtained easily.
One problem with natural products is trying to find databases of such compounds. Luckily in November of 2020, a Mexican group published a paper on fragment libraries and compound databases in the journal Biomolecules.5 Although it uses the IDs from the databases accessed, since they are all open, the name/structure can be located relatively easily. In addition, a “close companion” to the later paper is the review presentation by Sorokina and Steinbeck in Journal of Chemical Informatics published six months earlier.6 By using both of these, a substantial number of natural product-based molecules can be accessed.
REPURPOSING OF EXISTING DRUGS/ DRUG CANDIDATES
The concept of repurposing drugs or drug candidates is a well-known technique used in the hope of accelerating the drug approval process in the event that an existing entity will function in another disease. The rationale is that the toxicity and metabolism of the drug are known; all that must be shown is efficacy in the other disease in a relatively simple clinical trial.
There are two recent papers7, 8 published in Nature as accelerated articles that have demonstrated how, by using very modern informatic techniques, drug candidates can be identified that may be of utility as leads to potential drugs against SARS-CoV-2. In the first case,7 a group led by Krogan cloned, tagged and expressed 26 of the 29 SARS-CoV-2 “targets” in human cells and then identified 332 human protein-protein interactions. From these, 66 “druggable” human proteins, 69 of the approximately 13,000 candidate compounds culled from two main sources were further investigated yielding “inhibitors of mRNA translation and regulators of sigma 1 & 2 receptors.” Currently, this paper has been cited over 550 times, is freely available and supplementary Tables 4 and 5 are the essential ones as they show the literature-derived (37 compounds, Table 4) and expert-identified (32 compounds, Table 5). Both are downloadable as Excel files with structures. A very significant proportion are either NPs or fall into the ND categories of Newman and Cragg.
In the second article,8 which was received by Nature two days before the acceptance of the paper above, just under 12,000 compounds from the ReFRAME collection were assessed for their inhibition of virus replication in Vero E6 cells, leading to the identification of 100 molecules that had potential for inhibiting the virus. These were then further assessed in a number of secondary systems, leading to the identification of 13 that may well be of utility, as most already had moved into clinical studies. Currently, this paper has been cited nearly 70 times. Their supplementary Table 3 gives the data for 100 compounds that are 40% active or higher in Vero E6 cells. Although only names/code numbers and SMILES strings are given, a number are NDs. In their Table 4 they give information on their top 21 antiviral compounds. Again, there are a number of NDs and, as with the earlier paper, the complete paper can be freely downloaded.
The concept of repurposing drugs or drug candidates is a well-known technique used in the hope of accelerating the drug approval process in the event that an existing entity will function in another disease. The rationale is that the toxicity and metabolism of the drug is known; all that must be shown is efficacy in the other disease in a relatively simple clinical trial.
An interesting paper on the same topic, but this time looking at only the repurposing of anticancer drugs, was published by a multinational group (Morocco, Italy, Canada, Portugal) with El Bairi as the lead author.9 If one looks at their Table 1 which shows the current clinical trials for the agents identified again NPs and NDs are “present and correct!” Buried in this paper are significant comments on one well-known marine natural product under its trade name Plitidepsin (aka Aplidine) (2) and a small molecule, the modified rocaglate Zotatifin (3). What is very significant is that both of these compounds have an MoA attacking e1F4A.
The very interesting aspect of aplidine is that Pharma- Mar commenced clinical trials looking at toxicity with the aim of perhaps leading to another (repurposed!) use for this compound which has only been approved for multiple myeloma in Australia (late 2018). Normally I would not use the attached announcement from PharmaMar as a reference, but due to the potential of the current findings in ongoing clinical trials it should be recognized.10 A full paper describing the efficacy of aplidine preclinically was published very recently by the Krogan group in Science and is yet another example of the amount of interest in discovering molecules from other diseases that can be reprogrammed.11
Another interesting aspect is that aplidine is also known as dehydrodidemnin B and the didemnins were first discovered by the Rinehart group using “AN ANTIVIRAL ASSAY.” That these compounds had an effect on the e1F system was known quite a while ago but not followed up on. The actual source of aplidine has not been reported, but the didemnins are definitively from a free-living marine microbe as demonstrated back in 2011 and 2012. Both series of compounds have been synthesized, and aplidine has a synthetic cGMP production system used by PharmaMar.
The very interesting aspect of aplidine is that PharmaMar commenced clinical trials looking at toxicity with the aim of perhaps leading to another (repurposed!) use for this compound which has only been approved for multiple myeloma in Australia (late 2018).
The rocaglate Zotatifin is a semisynthetic agent in clinical trials and was identified in the Nature paper by Gordon et al.7 The antiviral data on this compound is referenced in El Bairi et al.9 Interestingly, the full story of the synthesis of this compound under the code eFT226 was published in 2020 by Ernst et al.12 The modified rocaglate CR-31-B(-) (4) also “fits the bill” as a CoV-2 inhibitor as shown by Muller et al.13 This molecule was synthesized and resolved as part of a major synthetic effort published in 2012.14
There was some discussion in the early literature referring to CoV-2 (currently there are multi-thousands of references in PubMed related to this virus) from initial infection data levels that people who had been inoculated with BCG (Bacillus Calmett-Guerin) as an anti-TB prophylactic might have some resistance to infection by CoV-2. Now comes the part where two completely independent groups came to the same conclusion, that this treatment either years ago, or currently, did not provide any obvious protection. The first paper was one that I was involved with together with some “colleagues from the past,” and it was published online by Letters in Applied Microbiology at the beginning of August 2020, followed by a formal publication.15 This was followed in late September 2020 by a “Letter in PNAS” by Arlehamn, Sette and Peters reporting the same, but without any citation to our earlier work.16
SUGGESTIONS FOR THE FUTURE
As a result of a request from the editor of Chemical Society Reviews, a “Viewpoint” article was put together by an international group led by Dorrington17 at Rhodes University in South Africa. It was designed to provide some history on what had been done with other viral epidemics and to make suggestions as to what can be done “by scientists” to try to avoid the problems that have arisen with CoV-2. Obviously, this was not designed to provide a single blueprint but more to make people think. The paper is an Open Access one and can be read and commented on by anyone who so desires.
There was some discussion in the early literature referring to CoV-2 (currently there are multi thousands of references in PubMed related to this virus) from initial infection data levels that people who had been inoculated with BCG (Bacillus Calmett-Guerin) as an anti TB prophylactic might have some resistance to infection by CoV-2. Now comes the part where two completely independent groups came to the same conclusion, that this treatment either years ago, or currently, did not provide any obvious protection. The first paper was one that I was involved with together with some “colleagues from the past,” and it was published online by Letters in Applied Microbiology at the beginning of August 2020, followed by a formal publication.15
Christy, M. P., Uekusa, Y., Gerwick, L. and Gerwick, W. H. Natural products with potential to treat RNA virus pathogens including SARS-CoV2+. J. Nat. Prod. 2020. doi 10.1021/acs.jnatprod.0c00968.
Schutz, D., Ruiz-Blanco, Y. B., Munch, J., Kirchhoff, F., Sanchez-Garcia, E., and Muller, J. A. Peptide and peptide-based inhibitors of SARS-CoV2-2 entry. Adv. Drug Del. Rev. 2020, 167, 47-65.
de Lira, S. P., Seleghim, M. H. R., Williams, D. E., Marion, F., Hamill, P., Jean, F., Andersen, R. J., Hajdu, E. and Berlinck, G. S. A SARS-coronavirus 3CL protease inhibitor isolated from the marine sponge Axinella cf. corrugata: Structure elucidation and synthesis. J. Braz. Chem. Soc. 2007, 18, 440-443.
Santibanez, M. G., Lopez-Lopez, E., Prieto-Martinez, F. D., Sanchez-Cruz, N. and Medina-Franco, J. L. Consensus virtual screening of dark chemical matter and food chemicals uncover potential inhibitors of SARS-CoV-2 main protease. RSC Adv. 2020, 10, 25089. doi: 10.1039/d0ra04922k.
Chavez-Hernandez, A. L., Sanchez-Cruz, N. and Medina-Franco, J. L. Fragment library of natural products and compound databases for drug discovery. Biomolecules. 2020, 10, 1518. doi: 10.3390/biom10111518.
Sorokina, M. and Steibeck, C. Review on natural products databases: where to find data in 2020. J. Chem. Inform., 2020, 12, 29. doi: 10.1186/s13321-020-00424-9.
Gordon, D. E. et al (124 more authors). A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature, 2020, 583, 459-468. doi: 10.1038/s41586-020-2286-9.
Riva, L. et al (43 more authors). Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing. Nature. 2020, 586, 113-119 doi: 10.1038/s41586-020-2577-1.
El Bairi, K., et al (8 more authors). Repurposing anticancer drugs for the management of COVID-19. Eur. J. Cancer. 2020, 141, 40-61. doi: 10.1016/j.ejca.2020.09.014.
PharmaMar PDF (see figure above).
White, K. M., et al (25 more authors, including 4 from PharmaMar). Plitidepsin has potent preclinical efficacy against SARS-CoV-2 by targeting the host protein eEF1A. Science. 2021. doi: 10.1126/science.abf4058.
Ernst, J. T. et al (22 more authors). Design of development candidate eFT226, a first in class inhibitor of eukaryotic initiation factor 4A RNA helicase. J. Med. Chem. 2020, 63, 5879-5955. 10.1021/acs.jmedchem.0c00182.
Muller, C. et al (8 more authors). The rocaglate CR-31-B (-) inhibits SARS-CoV-2 replication at non-cytotoxic, low nanomolar concentrations in vitro and ex vivo. Antiviral Res. 2021, 186, 105012. doi: 10.1016/j.antiviral.2021.105012.
Rodrigo, C. M., Cenic, R., Roche, S. P., Pelletier, J. and Porco, Jr., J. A. Synthesis of rocaglamide hydroxamates and related compounds as eukaryotic translation inhibitors: Synthetic and biological studies. J. Med. Chem. 2012, 55, 558-562. doi: 10.1021/jm201263k.
Wassenaar, T. M., Buzard, G. D. and Newman, D. J. BCG vaccination early in life does not improve COVID-19 outcome of elderly populations, based on nationally reported data. Lett. Appl. Microbiol. 2020, 71, 498-505.
Arlehamn, C. S. L., Sette, A. and Peters, B. Lack of evidence for BCG vaccine protection from severe COVID-19. Proc. Natl. Acad. Sci. USA. 2020, 117, 25203-25204. doi: 10.1073/pnas.2016733117.
Adamson, C. S., Chibale, K., Goss, R, J, M., Jaspars, M., Newman, D. J. and Dorrington, R. A. Antiviral drug discovery: preparing for the next pandemic. Chem. Soc. Rev. 2021. doi: 10.1039/d0cs01118e.