Abstract
Since the seminal breakthrough of treating diabetic patients with insulin in the 1920s, there has been great interest in developing other proteins and their peptide mimetics as therapies for a wide variety of other medical disorders. Currently, there are at least 60 different peptides that have been approved for human use and over 150 peptides that are in various stages of clinical development. Peptides mimetic of the major proteins on lipoproteins, namely apolipoproteins, have also been developed first as tools for understanding apolipoprotein structure and more recently as potential therapeutics. In this review, we discuss the biochemistry, peptide mimetics design and clinical trials for peptides based on apoA-I, apoE and apoC-II. We primarily focus on applications of peptide mimetics related to cardiovascular diseases. We conclude with a discussion on the limitations of peptides as therapeutic agents and the challenges that need to be overcome before apolipoprotein mimetic peptides can be developed into new drugs.
Highlights
There are more than a dozen different apolipoproteins, we will focus on three of the most important and well-studied peptide mimetics, namely those based on apolipoprotein A-I, apolipoprotein E, and apolipoprotein C-II
Much has been learned about lipoprotein metabolism from research related to apolipoprotein mimetic peptides and several of these peptides have moved into early stage clinical trials
Success into developing any of these peptides into an approved therapy will mainly depend on two factors, namely the validity of the target for the peptides and the pharmacokinetic and pharmacodynamic factors related to the delivery of the peptide
Summary
ApoA-I mimetic peptides have largely been designed based on their ability to efflux cholesterol from cells (Table 2). As this process has not been shown to depend upon a specific protein-protein interaction [17], most apoA-I mimetic peptides are just amphipathic helices and, many have no primary amino acid homology to apoA-I. The first of these peptides were designed in 1980s as structural probes for understanding lipoprotein assembly. Blocking N- and C-termina with acetyl and NH2 groups, respectively, increased its lipophilicity and helicity, by promoting the hydrogen bond formation of the peptide backbone [20]
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