Peptides as Drugs: Re-examination Perceived Wisdom in Drug Design

摘要

The development of safe and effective drugs always has been a challenge. Indeed most drugs have LD_(50)'s, and many have additional toxicities. Many small molecular scaffolds which posses "drug-like" properties have inherent toxicities and their uses are coupled with the development of tolerance. It is increasingly evident that the "classical" approach to drug design is limiting, and in general these drugs do not address the problems of treating most of our major diseases (prolonged and neuropathic pain, diabetes, cancer, heart disease, etc.) but only their symptoms. A new paradigm for drug design and development is needed, and given the lessons we are learning from comparative genomics and proteomics of normal vs. disease states, drug design and development will require new approaches. From this perspective, peptides offer many advantages. Currently there are over 40 peptide drugs on the market and many additional peptide mimetics; about 270 peptides are in various phases of clinical trials, and over 400 peptides are in advanced preclinical studies [1]. Among the advantages of peptides are: 1) nontoxic scaffold; 2) remarkable chemical landscape; 3) easily modified for proteolytic stability; 4) inherent manipulation for bioavailability; and 5) readily designed to cross the blood brain barrier and other barriers. Here we will re-examine perceived wisdom regarding peptide drug design, with special emphasis on those common beliefs that are wrong, and provide an illustrative example of the design of a family of multivalent peptide ligands that may treat prolonged and neuropathic pain states that currently have no effective treatment. It is interesting that in going from unicellular to multicellular life, especially animal life, most "small molecule chemistry" was dropped, probably due to their inherent toxicities. Instead amino acids, amino acid derivatives and peptides were chosen for intercellular communication. We should learn from Mother Nature! Despite the ubiquitous use of peptides for intracellular communication and maintenance of homeostasis, there is perceived wisdom that peptides have poor pharmacokinetic and pharmacodynamic properties. Of course many do, and were designed by Nature that way. But many do not, and Nature uses various chemical approaches to enhance these properties. We should learn from Mother Nature! Similarly perceived wisdom is that peptides do not cross the BBB. There are many solutions to this problem including: 1) stabilization of 3-D conformations, e.g. α helix or β-turns; 2) Nmethylation; 3) glycopeptides; 4) amphipathic peptides; 5) cell penetrating peptides; and 6) pcgylation etc.