The potential of apolipoprotein mimetic peptides in the treatment of atherosclerosis

Medical landscape There is a clear medical need for new approaches to treat cardiovascular disease. Especially useful would be treatments that are complementary to, but function through a different mechanism than, current LDLlowering agents. Despite the widespread use of statins to control LDL cholesterol levels and lessen the burden of cardiovascular disease, atherosclerosis remains a leading cause of death worldwide, and mortality from cardiovascular disease is expected to increase dramatically in developing countries over the coming decades. Fortunately, some help is on the way through new agents that are under clinical investigation, especially the widely recognized PCSK9 inhibitors, although these compounds function through the same basic LDL-lowering approach as currently prescribed drugs. In this context, improving or augmenting the function of HDL represents an attractive strategy for combating atherosclerosis. HDLs facilitate the process of reverse cholesterol transport (RCT) and exhibit other atheroprotective properties. The relation of HDL to atherosclerosis is extremely complex, and questions remain about how best to harness the potential of HDL for medical applications. Even so, HDLs appear to confer cardiovascular protection even among patients treated with statins who have achieved very low (<50 mg/dl) LDL cholesterol levels [1]. Importantly, HDL-mediated therapeutics would offer a mechanistically distinct approach from the LDL-lowering agents to combat cardiovascular disease. Apolipoprotein mimetic peptides Short synthetic peptides with sequences that mimic those found in natural apolipoproteins have been studied since the 1980s for their potential to generate HDL-like nanoparticles and improve the function of endogenous HDLs [2]. As their name implies, apolipoprotein mimetic peptides are designed to recapitulate the behavior of apolipoproteins, most often apoA-I or apoE, in promoting the formation and functions of endogenous lipoproteins, especially HDLs. Among the reported properties of apolipoprotein mimetic peptides are lipid-associating ability, activation of enzymes involved in HDL maturation and remodeling, promotion of cholesterol efflux, binding of oxidized lipids, anti-inflammatory and antioxidant effects, and inhibition of atherosclerosis progression in a variety of animal models. To date, several small human clinical trials involving apolipoprotein mimetic peptides have been reported [2]. Among the most important recent developments in the field of apolipoprotein mimetic peptides are: