Small and large molecules: drugs on a chemical and biological basis

One aspect of finding the right approach for a new treatment is choosing the best technology platform. Molecules used as active substances can be divided into two classes – small and large molecules. They differ not only in terms of size, but also in how they are made, how they behave, their mode of action in the body and their suitability for certain drug forms.

Small, chemically manufactured molecules (or SMOLs for short) are the classic active substances and still make up over 90 percent of the drugs on the market today. By contrast, large molecules – also known as biologics – are therapeutic proteins; they are becoming increasingly important.

Small molecules: the basis of classic drugs

Classic drug development works with small, chemically manufactured active-substance molecules. One example is acetylsalicylic acid (ASA), aspirin's active ingredient with a molecular weight of about 180 g/mol or 180 Da. These small molecules can be processed into easily ingestible tablets or capsules. If the tablet dissolves in the gastrointestinal tract, the dissolved active substance is absorbed into the bloodstream via the intestinal wall. From there, the small molecules can reach almost any desired destination in the body because of their tiny size. Their small structure and chemical composition often also helps them to easily penetrate cell membranes.

Small molecules are synthesized in the classic way: by chemical reactions between different organic and/or inorganic compounds. Small amounts of active substance for research are made in the chemistry lab using – among other things – the familiar round-bottom flasks and rotary evaporators. The last ten years have also seen the advent of new automated synthesis methods in research laboratories that enable chemists to conduct whole series of reaction mixtures in parallel (see also Combinatorial chemistry).

Bayer HealthCare's researchers use high-throughput screening to search for small molecules which can be used as a starting point (or lead compound) for a new drug. They use this automated, robot-based testing method to comb through our in-house substance library, which contains more than two million small molecules.

Biologics: pioneering drugs made of proteins

Biologics (or biopharmaceuticals) are a class of drugs based on proteins that have a therapeutic effect. These large protein molecules – which are composed of more than 1,300 amino acids and can be as heavy as 150,000 g/mol (or 150 kDa) – are essentially copies or optimized versions of endogenous human proteins.

Biologics bind to specific cell receptors that are associated with the disease process. Monoclonal antibodies are specialized in recognizing a very specific structure on the cell surface. Used in cancer therapy, they bind selectively – for example to the receptors of cancer cells, making it possible to mark and fight specific abnormal cells. Healthy cells are usually not attacked in this process, so that biologics often cause fewer side effects than classic chemotherapy.

Biologics researchers at Bayer also use antibodies as carrier molecules for toxic substances, with the aim of transporting cell poisons to their exact site of action – inside cancer cells – and not releasing them until they arrive there. Such combinations of antibodies and cell toxins are also known as antibody-drug conjugates.

Biopharmaceuticals are administered by injection or infusion – because if they were taken orally they would (like other proteins) be digested in the stomach and intestines, and therefore be ineffective (see also Galenics).

They are produced in biotechnological processes via genetically modified cells of microorganisms such as bacteria, or yeasts or in mammalian cell lines. Over 1,000 process steps may be necessary to assemble a complex protein.

The production of biologics for therapeutic use is preceded by an optimization process known as protein engineering, in which naturally occurring protein molecules are usually geared to a specific task. Before a protein can have its intended medical effect, the researchers at Bayer HealthCare have to alter its 'blueprint'. The amino acids are systematically exchanged until the biologic candidate functions even better than the natural variant: for example, it might bind more tightly or specifically to its target molecule. About 80,000 different variants of a protein that is to be optimized are tested every day. Here, too, this is made possible by fully automated, robot-based high-throughput screening and the use of special testing systems.

Biologics research has become increasingly important at Bayer HealthCare in recent years and is to be continuously expanded over the next few years. The medium-term objective is to increase protein therapeutic agents' share of Bayer's pipeline to a third of all projects.

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