Advantages and difficulties of peptides, small molecules and therapeutic proteins in drug development^1–6.

	Small molecules	Peptides	Therapeutic proteins
	MW < 500 Da	MW ∼ 500–5000 Da	MW > 5000 Da
Advantages	• Low cost in production and price on market	• Automated synthesis	• Very high target affinity, potency, specificity and selectivity due to large interaction site
	• Ease of synthesis	• High target affinity, potency, specificity and selectivity	• Long half life
	• Membrane permeability achievable, oral bioavailability and intracellular targets accessible	• No toxic metabolites	• Drug safety, no toxic metabolites
	• Known guidelines for drug design, Lipinski rule of 5	• Chemical synthesis enables easy structure modifications
Difficulties	• Often hepatic metabolism via CYP enzymes: prone to drug–drug interactions	• Proteolytic instabilitya	• Expensive in production and on market
	• Drug safety issues due to non-mechanistic-based toxicology (low affinity or selectivity)	• Rapid clearance, short half-lifea	• Complex (often recombinant) production, no easy chemical modification
	• Targets with need for large interaction sites precluded	• Low membrane permeabilitya due to high polarity, no intracellular targets, no CNS targets, no oral absorption	• Immunogenicity
		• No guidelines for rational drug design	• No/low membrane permeability due to size, parenteral administration (s.c./i.v.), only extracellular or surface-exposed targets
			• Chemically and physically unstable, elaborated storage (sensitive to heat, pH, oxidation)

^aChemically unmodified peptides.