The 2018 Nobel Prize in Chemistry was awarded for the development of methods for the directed evolution of peptides and proteins. Half of the prize went to George P. Smith and Sir Gregory P. Winter for their invention of phage display technology. What is its essence? How do bacterial viruses (bacteriophages) aid in the development of modern medicines?

Antibodies are important therapeutic agents, increasingly used to treat a wide variety of diseases, from rheumatoid arthritis and psoriasis to cancer. Highly specific antibodies bind to a target molecule and, for example, block its activity. However, selecting the right antibody for a specific substance is challenging. Currently, phage display is the most commonly used method for this purpose.

George Smith* was the first to propose using bacterial viruses (bacteriophages) to synthesize specific antibodies. He chose simply organized filamentous phages with a small number of genes. In 1985, he demonstrated that if a DNA fragment encoding another protein is attached to the phage coat protein gene in the same reading frame, the latter will be synthesized alongside the viral coat protein and will appear on the phage particle's surface after assembly. Smith also studied how the region where a new peptide sequence appears ("displays") depends on the location in the gene into which the new DNA fragment is inserted.

Five years after the publication of Smith's first paper, Gregory Winter succeeded in producing antibodies on the surface of a bacteriophage capable of specifically binding to a desired target antigen**. To do this, a gene encoding the desired antibody region required for antigen recognition is inserted into the phage DNA. The desired peptide then appears on the surface of the phage shell, and the virus essentially transforms into an antibody. Following this, a process of directed evolution is performed—random mutations are introduced into the DNA, thereby creating a library of viruses with thousands of variants of the gene encoding the antibody fragment. All these phages are then tested for binding to the antigen. The phage that binds most strongly is selected, and its DNA is sequenced. This allows one to determine the sequence of the gene encoding the peptide that effectively binds to the target.

Phage display is currently the fastest way to produce antibodies for medical use.

* Smith G.P. Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface // Science, 1985, 228(4705):1315-1317. DOI: 10.1126/science.4001944

** McCafferty J, Griffiths AD, Winter Greg and Chiswell DJ. Phage antibodies: filamentous phage displaying antibody variable domains // Nature, 1990, 348: 552–554. DOI: https://doi.org/10.1038/348552a0