Peptides and Oligonucleotides, common trends as drugs

Last year in this same forum, we affirmed that we are witnessing a golden age of peptides and oligonucleotides as pharmaceuticals (1). In this regard, from 1 January 2016 to 30 April 2023, the US Food and Drug Administration (FDA) approved 31 new drugs whose active pharmaceutical ingredients (APIs) contain peptides (Table 1). This list includes six radioactive peptide‐based thera/diagnostic agents and four antibody drug conjugates (ADCs) with a peptide drug.

The consolidation of peptides as a key class of new drugs was facilitated by three events that took place in 2022. First, in October, Professor Morten Meldal was awarded the 2022 Nobel Prize in Chemistry, together with Professors Barry Sharpless (La Jolla Scripps Research Institute) and Carolyn Bertozzi (Stanford University). Although the prize was given “for the development of Click (Huisgen cycloaddition) chemistry and bioorthogonal chemistry”, it is important to remember that Morten Meldal is a peptide chemist who has made significant contributions to the development of Fmoc chemistry and peptide-based nanotechnologies. After Vincent du Vigneaud (1955) and Bruce Merrifield (1984), Morten Meldal is the third peptide chemist to receive the Nobel Prize.

Second, Eli Lilly’s drug Tirzepatide (MounjaroTM) was approved by the FDA (5). Tirzepatide has agonist activity at two receptors, namely GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide), thus being a first-in-class drug. Tirzepatide is indicated for the treatment of type 2 diabetes and also obesity. In addition, it has shown highly satisfactory results for the treatment of non-alcoholic steatohepatitis (NASH). Its backbone contains 39 amino acids with two non-canonical α-aminoisobutyric acid (Aib) residues and one Lys residue where its side-chain is linked to the γ-carboxylic group of a Glu residue, which in turn is bound to two (2-(2-aminoethoxy)ethoxy)acetic acid residues and eicosanedioic acid (C20 diacid). Tirzepatide is one of the largest peptides on the market that is fully chemically produced by a hybrid solid-phase/solution strategy, where four fragments prepared in solid-phase are assembled in solution (6). The market forecast predicts annual sales of $10b per year for this drug, which will make it a blockbuster.