Enhancing the pharmaceutical properties of peptides
To begin the discussion about enhancing or improving pharmaceutical properties, one must first understand “the good, the bad, and the ugly” of peptides (1). The good. Peptides are generally highly potent, selective, and have a low potential for toxicity and low risk of drug-drug interaction. The bad. Peptides are generally not terribly stable in biological matrices, susceptible to protease degradation. The ugly. The polar nature of the peptide bond and the size of peptide molecules makes permeability across cell membranes challenging.
In small molecule drug development, we commonly think about Lipinski’s rule of five (2), which is based on the observation that most orally administered drugs have common physicochemical characteristics, namely,
- a molecular mass less than 500 daltons
- a logP (octanol-water partition coefficient) less than 5
- no more than 5 hydrogen bond donors
- no more than 10 (2 x 5) hydrogen bond acceptors.
Peptides violate each and every one of these rules, and hence the need to improve their pharmaceutical properties.
The focus of this paper is to summarize strategies that can make “the bad” into “the good” and perhaps even make “the ugly” into good or bad—enhancing the pharmaceutical properties of peptides.
From “the bad” to “the good”
There are numerous strategies to increase peptide stability including peptide conjugates with various polymer molecules (3).
PEGylation refers to the attachment of poly(ethylene glycol) or PEG to peptides or proteins and is able to improve the pharmacokinetic properties of these molecules ...