Day by day, we see that COVID-19 vaccines have the potential to dramatically decrease the severity of the disease. But we also realize that vaccination will be a long process, that there are deficiencies in the supply of vaccines, and that we are witnessing inequality and delay in most countries. Nor can we forget that, in the meantime, new variants may appear and that the duration of acquired immunity is still unknown.
In addition, even if we manage to tackle SARS-CoV-2 for now, outbreaks of the disease could appear periodically (as with Ebola). On the other hand, we cannot ignore millions of people who for various reasons cannot be vaccinated, because they have a compromised immune system, or because they fail to develop immunity against COVID-19 even with the complete vaccination schedule.
The solution to these problems would be to find a definitive treatment for the disease. Ideally it should be easy to access and apply (oral, for example) and eliminate or limit viral transmission. Posts to ask …
What is drug repositioning?
The traditional drug development process is a complex process that involves very long times and large investments. Therefore, from the beginning, the first resource was to use drugs already established in terms of speed and safety that could be used to combat a new pathology such as COVID-19. What is known as drug repositioning.
The repositioning process helps speed up the development of a drug as several stages are eliminated. For example, preclinical studies evaluating the safety of drugs prior to approval by regulatory agencies for transition to clinical trials. Also, when a drug is already on the market and is routinely used for other diseases, Phase I clinical trials can be eliminated, saving a lot of time, effort and money.
Shortening the time is always important, but in situations like the current pandemic that we are experiencing, it is of great need.
Current treatments are repositioned, but they are not definitive.
Despite great efforts, therapy options for COVID-19 remain quite limited. Doctors give corticosteroids (dexamethasone) and remdesivir (an antiviral compound against Ebola) intravenously for critical cases.
The first treatments with hydroxychloroquine, lopinavir and interferon, ivermectin, aplidine, colchicine or antitumor drugs, to which monoclonal antibodies must be added, and the more than 300 registered clinical trials have not shown definitive results. The conclusions of the international multicenter trials Solidarity (WHO) and Recovery (UK) have found evidence of improvement in favor of dexamethasone alone.
Are we facing a failure? Not quite.
The scientific community continues to research specific treatments directly directed against SARS-CoV-2 and also to search both known libraries (collections) of compounds (such as the FDA drug library) and engineered libraries.
The limited success among candidates for high-value drugs that are reused for SARS-CoV-2 infection reflects the shortage of advanced and approved antiviral and anti-infective compounds, and further highlights the need for research into new drugs of this type.
How have other potential candidates been found?
From thousands of known molecules, researchers try to find a needle in a haystack: a compound for which a specific activity that prevents the development of the disease is demonstrated and validated.
Very recently, a group of researchers from the Scripps Research Institute (La Jolla, USA) has developed a massive phenotypic screening methodology in order to identify known drugs.
They use two compound libraries: a “pilot library” of 148 known drugs with potential coronavirus activity and the ReFRAME (Reporpousing, Focused Rescue and Accelarated MedChem) library with more than 12,000 drugs. This latest collection consists of three widely used commercial drug databases (Clarivate Integrity, GVK Excelra GoStar, and Citeline Pharmaprojects), along with a large group of patent-derived compounds that have been used in humans – over 12,000 molecules!
The search for the needle in the haystack –or screening protocol, as it is called in scientific jargon– is made up of different experimental tests that are visualized in Figure 1.
The first two filters consist of two infection assays in cultured cells: HeLa cells that express the SARS-CoV-2 receptor ACE2 and Calu-3 lung epithelial cells where they are expressed in addition to the ACE2 receptor, TMPRSS2.
From testing the 12,000 compounds of the two libraries, 49 (in HeLa-ACE2) and 41 (in Calu-3) compounds capable of selectively inhibiting the replication of SARS-CoV-2 were identified. Less than 1% of the initial molecules.
Among the most promising compounds, the researchers identified from the “pilot library” the antivirals nelfinavir and the prodrug MK-4482. Both reduce the replication of SARS-CoV-2 in primary cultures of human bronchial epithelial cells (filter 3). These two compounds are known drugs, so they have a good absorption, activity and safety profile in humans.
Subsequently, compound MK-4482 was studied in an animal model (filter 4), verifying that it effectively blocks SARS-CoV-2 infection.
The efficacy of compound MK-4482 is currently being studied in clinical trials II / III (Ridgeback Biotherapeutics and Merck) to evaluate safety and efficacy. Less than 0.01% with respect to the starting molecules.
Vaccines have allowed us to breathe and see the light at the end of the tunnel, but we must not forget that effective drug treatments are needed to treat COVID-19.
A serious effort is being made by the scientific community to identify both repositioning and new generation drugs. The important thing is to get an arsenal of antivirals capable of fighting this virus. And if incidentally they serve us for other futures, then better than better.
María Mercedes Jiménez Sarmiento, CSIC Scientist. Systems Biochemistry of the bacterial division. Scientific communicator, Margarita Salas Biological Research Center (CIB – CSIC); Matilde Cañelles López, Scientific Researcher. Science, Technology and Society, Institute of Philosophy (IFS-CSIC) and Nuria Eugenia Campillo, Senior Scientist. Medicinal Chemistry, Margarita Salas Biological Research Center (CIB – CSIC)
This article was originally published on The Conversation. Read the original.
