Early Discovery Target ID
Molecules used for pharmaceuticals can be divided into two types – small and large molecules. Large molecules and small molecules differ in terms of size, how they are made, how they function in the body, and their suitability for certain drug forms. Small, chemically manufactured molecules are the classic active substances used in pharmaceuticals Large molecules – also known as biologics – are therapeutic proteins.
Small molecules are synthesized by chemical reactions between different organic and/or inorganic compounds. Easily ingestible pills, small molecules dissolve in the gastrointestinal tract and are absorbed into the bloodstream via the intestinal wall. Due to the small size, once in the bloodstream, small molecules can reach almost any desired destination in the body. Small molecules also have a small structure and chemical composition allowing them to penetrate cell membranes.
Biologics are agents obtained from, synthesized in, or constructed using biological sources. Biological agents include fluids (blood and blood components), solids (tissues, feces), proteins (vaccines, antibodies), cells, or genetic material. The primary difference between biologic agents and traditional pharmaceuticals is that the former are substances either extracted or produced from biological entities, while the latter are totally synthesized from molecular components via chemical reactions.
Biologics can be artificially designed or altered – CAR-T cells, containing an artificially designed and assembled chimeric antigen receptor expressed by selected and expanded cells initially derived from a biological source, are a perfect example of how laboratory manipulations take biological components and assemble them into an agent. Biologics can also incorporate synthetic elements – for example, a synthetic nanoparticle can be used as a vector for a biologic.
As biological entities, biologics are subject to more inherent variability (in form, function, and efficacy) than totally synthesized pharmaceuticals. They are also more susceptible to small changes in environmental conditions, whether during production, storage, or use. These factors contribute to an increased level of uncertainty surrounding biologics versus traditional pharmaceutical agents (which have known and well-defined structural and kinetic properties). Biologics are therefore subject to different quality control/assurance regulatory standards than traditional pharmaceutical agents.
For both synthetic and biological agents, bringing an agent from the bench to the bedside is a long and arduous process, usually taking well beyond 10 years of work and costing billions of dollars.1,2 The process is fraught with trial and error, with only a minute fraction of the initially proposed candidates eventually proving suitable for clinical use.2 While the process required to deliver new agents to the researcher’s toolbox is not as long or as costly, many of the steps, especially the early ones, are the same.
Needle in a Haystack: Identifying New Biological Agents
The identification of a potential agent candidate first requires the identification and validation of a potential target. This process entails extensive laboratory experimentation using cellular, genetic, and in vivo techniques–first to search for possible targets, and second, to evaluate whether target modulation is efficacious and feasible for research purposes.1 Target identification has been greatly expedited by the increasing utility and accessibility of bioinformatics and big data, with genetic and phenotypic screening popularly employed. Similarly, validation strength and legitimacy has been enhanced by the promotion of multi-validation approaches that have been made feasible by increased accessibility to both the existing body of literature on any given topic and a variety of different potential validation techniques.1
After a potential target has been identified and validated, the next step is to locate and/or design an agent to modulate the target. Given the complexity of biological systems, proposed targets are almost never endogenously inert, and these natural mechanisms immediately provide researchers with potential candidate agents. Often, however, researchers will have to devise non-endogenous mechanisms of target modulation. For example, the premise of antibody therapy is based on the ability to derive antibodies capable of selectively targeting molecules that the body normally does not. Likewise, CAR-T cell therapy is predicated on the artificial redirection of T cell-targeting to antigens that would not be naturally considered.
- J.P. Hughes et al., “Principles of early drug discovery,” Br J Pharmacol, 162(6):1239-1249, 2011.
- R.C. Mohs and N.H. Greig, “Drug discovery and development: Role of basic biological research,” Alzheimers Dement (N Y), 3(4):651-657, 2017.