Novel fatty acyl apoE mimetic peptides have increased potency to reduce plasma cholesterol in mice and macaques.

Ac-hE18A-NH2 is a dual-domain apoE mimetic peptide that possesses the putative receptor binding domain from apoE (LRKLRKRLLR, denoted hE; residues 141-150) covalently attached to lipid-associating peptide 18A. Like apoE, Ac-hE18A-NH2 reduces plasma cholesterol in animal models and exhibits anti-inflammatory properties independent of its cholesterol-reducing effect. Ac-hE18A-NH2 has already undergone phase I clinical trials as a lipid-lowering agent. To explore the therapeutic potential more, we designed and synthesized new analogues by linking ɑ-aminohexanoic acid, octanoic acid, or myristic acid to LRRLRRRLLR-18A-NH2 ([R]hE18A-NH2) and examined the cholesterol-lowering potency in animals. The modified peptides effectively reduced plasma cholesterol in apoE-null mice fed standard chow or a Western diet; the myristyl analogue was the most effective. A single administration of the myristyl analogue reduced plasma total and LDL cholesterol in a dose-dependent manner in hypercholesterolemic cynomolgus macaques for up to 1 week despite the continuation of a cholesterol-supplemented diet. The myristyl peptide (7.4 mg/kg) reduced total and LDL cholesterol at 24 h by 64% and 74%, respectively; plasma HDL levels were modestly reduced and returned to baseline by day 7. These new analogues should exhibit enhanced potency at lower doses than Ac-hE18A-NH2, which may make them attractive therapeutic candidates for clinical trials.

Recent developments in modulating atherogenic lipoproteins.

PURPOSE OF REVIEW: Randomized clinical trials have assessed the effects of several classes of drugs on plasma cholesterol levels in patients with coronary artery disease. Agents including niacin, fibrates and statins significantly lower LDL-cholesterol, but tolerance issues and undesirable side-effects are common. Residual risk may also be present in patients with persistently low HDL-cholesterol despite a reduction in LDL-cholesterol. Recent trials of drugs that increase circulating HDL-cholesterol have also been disappointing. RECENT FINDINGS: Ongoing efforts target the development of new pharmacotherapies to reduce circulating levels of atherogenic lipoproteins. The goal of this review is to discuss recent advances in the treatment of coronary artery disease and other vascular diseases characterized by an increase in circulating atherogenic lipoproteins. These include the development of inhibitors of ATP citrate lyase and proprotein convertase subtilisin/kexin type 9. We also discuss recent developments in HDL therapy, including the clinical assessment of cholesteryl ester transfer protein inhibitors and apolipoprotein E mimetic peptides. SUMMARY: Several new classes of drug are undergoing clinical evaluation that show promise for atherogenic lipoprotein reduction in patients who are statin intolerant.

Topical iontophoretic administration of acyclovir for the episodic treatment of herpes labialis: a randomized, double-blind, placebo-controlled, clinic-initiated trial.

BACKGROUND: Multiple studies of the use of acyclovir for the treatment of herpes labialis have suggested that the nominal efficacy of the topical formulation is the result of inadequate penetration of the drug into the target site of infection, the basal epidermis. METHODS: We developed a low-voltage, wireless, hand-held, computer-controlled, iontophoretic applicator to enhance the skin penetration of topical acyclovir in the treatment of herpes labialis. We performed a multicenter, placebo-controlled, clinic-initiated, pilot trial of a single, topical, iontophoretic application of 5% acyclovir cream for the episodic treatment of herpes labialis among 200 patients with an incipient cold sore outbreak at the erythema or papular/edema lesion stage. RESULTS: The median classic lesion healing time (aborted lesions were assigned a value of 0 h) was 1.5 days shorter for the active treatment group than for the vehicle group (113 h vs. 148 h; P = .02). In the subgroup of patients who presented with lesions in the erythema stage, the median classic lesion healing time was 3 days shorter for the acyclovir group, compared with the control group (49 h vs. 120 h; P < .03), and the acyclovir group tended to have more aborted lesions than did the control group (46% vs. 24%; P = .10). CONCLUSIONS: Single-dose topical iontophoresis of acyclovir appears to be a convenient and effective treatment for cold sores and merits further clinical investigation.

Novel method for reducing plasma cholesterol: a ligand replacement therapy.

Despite wide use of statins, significant cardiovascular disease risk persists. High-density lipoprotein based therapy has not yielded any positive results in combating this disease. Newer methods to rapidly decrease plasma cholesterol are much needed. While apolipoprotein B is a ligand for low-density lipoprotein receptor, which clears low-density lipoprotein cholesterol in a highly regulated pathway, apolipoprotein E (apoE) is a ligand for clearing other apolipoprotein B containing atherogenic lipoproteins via an alternate receptor pathway, especially the heparin sulfate proteoglycans on the liver cell surface. We describe here a novel method that replaces apoE as a ligand to clear all of the atherogenic lipoproteins via the heparin sulfate proteoglycans pathway. This ligand replacement apoE mimetic peptide therapy, having been designated as an orphan drug by the US FDA, is in clinical trials.

Apolipoprotein E mimetics and cholesterol-lowering properties.

Apolipoprotein E (apoE) is a ligand for clearance of lipoprotein remnants such as chylomicrons and very low-density lipoproteins. It has anti-atherogenic and anti-inflammatory properties. Therefore, there is extensive ongoing research to create peptides that can mimic properties of apoE. A number of synthetic peptides that encompass different regions of apoE have been studied for inhibiting inflammatory states, including Alzheimer disease. However, peptides that clear atherogenic lipoproteins, analogous to apoE, via enhanced hepatic uptake have not been previously reviewed. Toward this end, we describe the design and studies of a dual-domain apoE mimetic peptide, Ac-hE18A-NH(2). This peptide consists of residues 141-150, the putative receptor-binding region of human apoE, covalently linked to a well characterized class A amphipathic helix, 18A, which has no sequence homology to any other exchangeable apolipoprotein sequences. It demonstrates dramatic effects in reducing plasma cholesterol levels in dyslipidemic mouse and rabbit models. We discuss the scientific rationale and review the literature for the design and efficacy of the peptide. Analogous to apoE, this peptide bypasses the low-density lipoprotein receptor for the hepatic uptake of atherogenic lipoproteins via heparan sulfate proteoglycan (HSPG). ApoE mimetics such as Ac-hE18A-NH(2) may therefore restore or replace ligands in genetically induced hyperlipidemias to enable reduction in atherogenic lipoproteins via HSPG even in the absence of functional low-density lipoprotein receptors. Therefore, this and similar peptides may be useful in the treatment of dyslipidemic disorders such as familial hyperlipidemia and atherosclerosis.