COVID-19: "Renaissance" of Small Molecules.

Research into a drug against SARS-CoV-2 is giving small molecules a renaissance.

The research for a drug against COVID-19 has led to a renaissance of small molecules. This article looks at small molecules from their discovery to the present day.

The origin.

We are in Rome in 1893, where the Roman physician and microbiologist Bartolomeo Gosio was investigating the vitamin deficiency disease pellagra, the cause of which he suspected was a fungal infection of maize. In the process, he isolated one of the first medicines of "biological" origin from a mould of the genus Penicillium (presumably Penicillium Brevicompactum).[1] According to his observations, the crystalline mycophenolic acid isolated by Gosio inhibited the growth of the anthrax pathogen (Bacillus anthracis). Gosio published the corresponding study in 1896 (Figure 1).[2]

Structure of mycophenolic acid
Figure 1: Structure of mycophenolic acid.

While Gosio has probably been almost completely forgotten nowadays due to his lack of English skills, Alexander Fleming has remained in the history of the world to this day. The Scottish physician and bacteriologist rediscovered penicillins in 1922.[3]
At the beginning, however, his research received little attention. It was not until the Second World War that his groundbreaking discovery made its breakthrough. As was so often the case, mass production of the active ingredient subsequently proved difficult. It was not until the USA also began searching for a suitable strain of fungus that produced penicillin in larger quantities and developed a method of cultivating the fungus by fermentation that large-scale field trials became possible. Penicillin subsequently enjoyed great success on the battlefields of North Africa. From 1944, production was also able to supply the civilian population. Alexander Fleming received the Nobel Prize in Medicine for his discovery in 1945.

The triumphal march of the so-called antibiotics (substances that inhibit the growth of microorganisms/bacteria) and their further developed derivatives and analogues began.


In 2020, the world's population is facing major challenges. The novel coronavirus SARS-CoV-2 dominates the daily lives of everyone around the globe. The virus, which is spreading rapidly, has claimed several thousand lives worldwide to date.[4]

A race has begun worldwide to develop a promising therapeutic approach. Projects for antibodies for passive immunisation, studies for the new development of suitable active agents or vaccines up to the reuse or "bringing into the race" of already existing - in another context approved - antiviral drugs. This rapid way of having a SARS-CoV-2 antiviral drug available in a timely manner is based on a "repurposing" approach. The advantage is that both preclinical and clinical safety profiles are available in principle, but not yet in the context of SARS-CoV-2 infection, or COVID-19 disease. In this context, a large number of already established, so-called small molecules are currently being tested and the latter have almost experienced a small renaissance in recent months.

Small Molecules Medicines Versus Biological Medicines.

Speaking of the race! What is the difference between the so-called small molecules and their competitors, the biologics, and what does this have to do with the current situation?

Small molecules ("small molecules", or NCE, "New Chemical Entities") are organic low-molecular compounds with a molecular weight of up to 1 kDa. They influence or regulate biological processes. A considerable number of pharmaceutically active substances fall under the category of small molecules. Their applications in humans in the finished pharmaceutical product are diverse.

For example, they serve as medicines in medicine or as pesticides in agricultural science. These molecules are usually synthesised step by step in stirred tanks with a capacity of several thousand litres in organic solvents under optimally adjusted reaction conditions and isolated via controlled crystallisation. Their mass, industrial production is not costly.

Biologics, on the other hand, are drugs that are produced using recombinant biotechnology and genetically modifiedorganisms(GMO). Fermenters or bioreactors are used for this purpose.
Biologics have a molecular weight of 1 kDa or more, are generally polar and sensitive to heat. Compared to small molecules, their structure is considerably more complex. Producing large quantities (on a scale of several kilograms) is very complex and many times more time-consuming and cost-intensive than the production of small molecules. In particular, so-called therapeutic antibodies (these are large macromolecular biologics), which have a specific binding property to certain target molecules, are used predominantly in oncology for the treatment of tumours, but also in autoimmunity for the treatment of chronic autoimmune diseases.[5]

Advantages and disadvantages of the two groups.

In recent years, a real competition has broken out between these two product categories. Both groups have their specific areas of application and advantages and disadvantages.

Small molecules were considered a relatively simple business in the meantime, which seemed to have almost exhausted its potential, especially in the context of protein kinase inhibitors. Protein kinases are enzymes that transfer certain molecules (phosphate groups) to specific target molecules with energetic effort and thus activate them. Small molecules were developed in such a way that the phosphate group transfer of certain, specific protein kinases is inhibited and thus these so-called protein kinase inhibitors can be widely used in oncology for the treatment of tumours.[6]

Small molecules, on the other hand, are widely used in everyday life. Two of the best-known representatives are probably Efavirenz, a chiral drug that belongs to the group of non-nucleoside reverse transcriptase inhibitors (NNRTI) and is used to treat HIV-infected patients.[7] Another is valsartan, from the group of AT1 antagonists, and is used to treat hypertension or mild to moderate heart failure (Figure 2).[8]

Structures of efavirenz (left) and valsartan (right).
Structures of Efavirenz (left) and Valsartan (right).

Looking at facts and figures, the U.S. Food and Drug Administration (U.S. FDA) approved a total of 262 New Chemical Entities (NCEs) between 2010 and 2017. Of these, approximately 75% were small molecules and 25% were biologics.[9]

However, if one looks at the price of the two product categories - biologics are significantly more expensive than small molecules - the picture is different in terms of sales figures and application spectrum.

In the period from 2011 to 2017, sales revenues from biologics increased by a full 70% to 232 billion USD. The overall share of the pharmaceutical market grew from 16% in 2006 to 25% in 2016, with no signs of flattening or diminishing in the future.[10]

Nevertheless, enormous effort continues to flow into research and development of small molecules, especially in therapeutic areas such as Crohn's disease, ulcerative colitis, Parkinson's disease, hepatitis C or leukaemia. Major areas such as oncology, immunology, neurology and virological and bacteriological infectious diseases also remain in focus.

Why this circumstance is now to our advantage.

Today, the largest pharmaceutical companies can draw from a huge portfolio of small molecules to begin initial test applications in patients suffering from SARS-CoV-2.
Four potential antiviral candidates have been declared favourites.
The shortlist includes several "repurposed drugs" that have already been tested in humans and have all passed preclinical and clinical trials. The most advanced drug is probably 1) Remdesivir from Gilead.[11] This is a nucleoside analogue that was developed for use against Ebola infections because of its virostatic properties (Figure 3).

Structure of remdisivir
Structure of Remdisivir

Other candidates are 2) favipiravir and 3) chloroquine (Figure 4).[12][13]

Favipiravir, T-705, is a virostatic drug used against infections with various RNA viruses. It belongs to the group of pyrazine carboxamides and was used during the Ebola fever epidemic. Chloroquine, a quinoline derivative, is used as a drug for the therapy of malaria, but also for certain inflammatory rheumatic diseases, including Systemic Lupus Erytematosus (SLE).[14][15]

Structure of Favipiravir
Structure of chloroquine
Structure of Favipiravir

The fourth drug currently under consideration is the repurposed protease inhibitor Camostat.[16] It is approved in Japan as Foipan and is used for the oral treatment of chronic pancreatitis, pancreatitis and salivary gland inflammation (Figure 5).

Camostat is a functionalised derivative of p-aminobenzoic acid. Camostat inhibits in vitro various pancreatic proteolytic enzymes as well as the hydrolytic activity of C1r and C1 esterase. Furthermore, it inhibits cellular TMPRSS2, a membrane-bound protease needed by SARS-CoV-2 to enter the cell.[17]

Structure of camostat
Camostat structure

Summary and outlook.

This brief overview shows how important research and development on potent small molecules still is. Both groups, small molecules and biologics, have their raison d'être. They each have many advantages that the other product group cannot provide, which means that small molecules and biologics often find complementary applications. The world is not black or white in this respect!

Against the background of increasing observations of supply shortages of urgently needed small molecule type drugs and the current opportunity to develop new drugs or to produce and test "repurposed drugs" against COVID-19, a decisive contribution of pharmaceutical manufacturers is desirable to bring drug production back to Europe.[18]

Germany and Switzerland, as "strongholds" of the pharmaceutical-chemical industry, should take a pioneering role here and initiate this step. Continuous research on active pharmaceutical ingredients, whether small molecules, biosimilars, generics or other biologics, are existential and should always remain accessible and available without great dependencies on other, not always predictable partners.

  1. [1]a) B. Gosio et al, Giornale della Reale Accademia di Medicina di Torino 1893, 61, 484; b) B. Gosio et al, Archives Italiennes de Biologie 1893, 18, 253.
  2. [2]B. Gosio et al, Rivista d'Igiene e Sanità Pubblica 1896, 7, 484.
  3. [3]A. Flemming et al, Proceedings of the Royal Society of London. Series B. 1922, 93, 306.
  4. [4]; Accessed 22 April 2020.
  5. [5] Citation: "Monoclonal antibodies - a proven and rapidly expanding therapeutic modality for human diseases". Protein Cell 2010, 1, 319-330.; accessed 23 April 2020.
  6. [6]Citation: "Approved and experimental small-molecule oncology kinase inhibitor drugs: a mid-2016 overview. Medicinal Research Reviews, 2017 - Wiley Online Library.; accessed 23 April 2020.
  7. [7]a) A. Lilian et al, Synthetic Communications 1997, 27, 4373;
    b) M. E. Pierce et al, Journal of Organic Chemistry, 1998, 63, 8536.
  8. [8]S. Ghosh et al, Beilstein Journal of Organic Chemistry 2010, 6, 27.
  9. [9];
    Accessed 22 April 2020.
  10. [10]; Accessed 22 April 2020.
  11. [11]a) T. K. Warren et al, Nature 2016, 531, 381; b) M. K. Lo et al, Scientific Reports 2017, 7, 43395;
    (c) E. De Clercq et al, Chemistry, An Asian Journal 2019, 14, 3962; d) E. P. Tchesnokov, Viruses 2019, 11, 326; e) M. Wang, Cell Research 2020, 30, 269.
  12. [12]a) Y. Furuta et al, Antiviral Research 2009, 82, 95; b) T. Baranovich et al, Journal of Virology 2013, 87, 3741; c) F. Shi et al, Drug Discoveries and Therapeutics 2014, 8, 117.
  13. [13]a) J. Gao et al, BioScience Trends 2020, doi:10.5582/bst.2020.01047; b) C. Jun et al, Journal of Zhejiang University Medical Sciences 2020, doi:10.3785/j.issn.1008-9292.2020.03.03; c) P. Gautret et al, International Journal of Antimicrobial Agents 2020, doi:10.1016/j.ijantimicag.2020.105949.
  14. [14]Citation: "Clinical evidence and immunologic actions". J. Autoimmun. 2016, 74, 73.; accessed 1 May 2020.
  15. [15]Citation: "Perspective Piece Malaria Elimination: Time to Target All Species". Am. J. Trop. Med. Hyg. 2018, 99, 17.;
    Accessed 1 May 2020.
  16. [16]S. Fujii et al, Biochimica et Biophysica Acta- Enzymology 1981, 661, 342.
  17. [17]Hoffmann et al, "SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor". Cell 2020,,; accessed 22 March.2020.
  18. [18]R. D. Hess et al, "Drug shortages - A Critical Appraisal: The generics supply chain from the perspective of the German pharmaceutical generic drug industry". RAPS Regulatory Focus, Manuscript submitted on April 28th, 2020.

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Persons to the article.

Dr Ralf Hess

Principal Management Consultant

Dr Ralf Hess studied biology at the Albert-Ludwigs-University of Freiburg and received his doctorate at the Institute of Virology. Dr. Hess has many years of experience in the development of medical devices and medicinal products as well as their combination, in laboratory analytics and their quality assurance. The quality expert has established, implemented and maintained QM systems according to ISO and GxP for various application areas. The customer service portfolio ranges from manufacturers of classical and biological drugs, medical device companies and vaccine manufacturers to immunohistochemical, immunological, molecular biological and serological diagnostic laboratories. Dr. Hess is active worldwide as an auditor in the GxP/ISO area and has many years of experience in FDA remediation projects and the regulatory development of combination products (drug device products).
Dr. Ralf Hess supports Entourage as Principal Management Consultant.


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