Peptides: protein-like precision, small-molecule echoes
A therapeutic peptide is a short chain of amino acids — bigger than a small molecule, far smaller than a protein. Peptides can present a large, specific binding surface, which makes them well suited to disrupting protein–protein interactions that defeat small molecules. Insulin and the GLP-1 drugs are peptides. But two weaknesses dog them: they are chewed up quickly by proteases in the body (poor metabolic stability and short half-life), and they are too large and polar for good oral bioavailability.
Chemistry fights back. By swapping natural amino acids for unnatural ones, stapling the chain, or building a macrocycle (a closed ring), chemists block the proteases and stiffen the shape. A peptidomimetic goes further, mimicking a peptide's key contacts with a more drug-like, stable skeleton. These tricks have pushed a few peptides into once-weekly injections and even oral forms.
Oligonucleotides: drugging the message, not the protein
An oligonucleotide therapeutic is a short strand of DNA or RNA, designed to recognise a target by base-pairing — the same A-with-T, G-with-C logic that runs genetics. Instead of blocking a finished protein, it acts one step upstream, on the messenger RNA. An antisense oligonucleotide binds its complementary mRNA and either flags it for destruction or alters how it is spliced. An siRNA hijacks a natural cellular machine (RISC) to chop up the matching mRNA.
The huge advantage: design is almost programmable. Once you know the gene sequence, you know the drug sequence — you can target proteins that have no pocket at all, because you never touch the protein. The catch is delivery. Naked oligonucleotides are unstable and can't enter most cells. Chemists solve this two ways: by modifying the backbone (phosphorothioate links, sugar modifications) for stability, and by attaching a targeting tag such as GalNAc that ushers the drug specifically into liver cells.