D-4F
A small synthetic mimic of HDL's main protein, built from mirror-image amino acids so it survives the gut, tested by mouth in two phase 1 trials
D-4F is an 18-amino-acid peptide designed to behave like apolipoprotein A-I, the main protein of HDL cholesterol. It is made from D-amino acids, the mirror images of the ones in the body's proteins, which protects it from digestion. In mice and monkeys a drink of it made HDL less inflammatory and slowed or reversed artery plaque, especially with a statin. In two small phase 1 trials in people with heart disease it was safe, barely reached the blood, and still lowered a laboratory measure of HDL inflammation. It has never gone further and is not a medicine anywhere.
Used in human trials: 100, 300 or 500 mg, Once daily, Oral (Study: high-risk coronary patients on statins, 13-day multiple-dose...) Details ↓
Recommended Dosing
Used in human trials
No manufacturer dose exists for this use: these are amounts given in published trials, not recommendations.
What is it?
HDL particles carry cholesterol away from artery walls, and their main protein, apolipoprotein A-I (apoA-I), does much of that work. HDL can also turn harmful: during inflammation it collects oxidised fats and loses its ability to protect LDL. Researchers at the University of California, Los Angeles designed a family of short peptides that fold into the same kind of helix as apoA-I's lipid-binding segments. The version numbered 4F has four phenylalanines on its oily face. Built from ordinary L-amino acids it is digested in the gut, so they also made it from D-amino acids, the mirror-image building blocks that digestive enzymes cannot cut. That version is D-4F.
A 2005 review from the same group explains the idea. Peptides with the same amino acids in a slightly different order behaved very differently, and the active ones were those whose oily face grabbed oxidised lipids. When D-4F was given by mouth to mice and monkeys, it caused small, lipid-poor HDL particles to form, raised the activity of the HDL enzyme paraoxonase, lowered lipid hydroperoxides, and turned HDL from pro-inflammatory to anti-inflammatory in a test using human artery wall cells. Added to human plasma at very low concentrations, it did the same.
Animal studies followed in many directions. In mice prone to atherosclerosis, oral D-4F with a statin, each given at a dose too small to work alone, prevented plaque in young mice and shrank established plaque in old ones. It slowed plaque in diabetic mice, protected arteries during influenza infection, restored blood-vessel relaxation, and in single studies helped mouse models of Alzheimer's disease, stroke and asthma. One study found that the amount swallowed or injected, not the level reached in blood, decided how well it worked, and that the peptide ended up in the gut whichever route was used. That pointed to the intestine as a main site of action.
Two phase 1 trials tested it in people with coronary heart disease or an equivalent risk. In the first (2008), single doses by mouth were safe, plasma levels were low and lower still with food, and the HDL inflammatory index improved for a few hours at the two highest doses. In the second (2017), 62 patients on statins took it or a placebo daily for 13 days; the two higher doses roughly halved the HDL inflammatory index eight hours after dosing, and the effect tracked the dose swallowed rather than the amount in plasma. Neither trial changed cholesterol levels, and neither measured heart attacks, strokes or plaque.
No trial has gone past phase 1. A version made from L-amino acids, L-4F, was given by vein or under the skin to heart patients in two other studies and did not improve HDL function despite high blood levels. That is a different molecule and its results are listed in References only. D-4F itself is not approved anywhere, and the amounts below are from the two trials, not a recommendation.
Mechanism of Action
D-4F copies the lipid-binding helix of apolipoprotein A-I without sharing its sequence. Its oily face takes up oxidised lipids, and the evidence points to the gut as one place where it does this.
Soaking up oxidised lipids
It lowers lipoprotein lipid hydroperoxides and raises paraoxonase activity in mice (PMID 15197147), and blocks the formation of pro-inflammatory oxidised phospholipids in infected human lung cells (PMID 15533864).
Remodelling HDL
In mice it rapidly forms small pre-beta HDL particles and speeds cholesterol removal from macrophages (PMID 15197147), partly through the transporter ABCA1 (PMID 20208418).
Action in the intestine
In the 2017 human trial its effect on HDL followed the dose swallowed rather than the blood level, suggesting it need not reach the blood in quantity (PMID 28795506).
Artery lining
Restores nitric-oxide-dependent artery relaxation and heme oxygenase-1 signalling in rodents (PMIDs 16224061, 28767201).
Published Research
These are studies of D-4F itself, read from their PubMed abstracts: the two phase 1 trials in heart patients, two reviews by its developers, animal studies of atherosclerosis and other diseases, and cell studies of how it works. Trials of L-4F, the same sequence made from ordinary amino acids, are a different molecule and are listed under References only.
First multiple-dose trial: HDL inflammation halved
62 high-risk coronary patients already on a statin took placebo or D-4F by mouth daily for 13 days, in cohorts of 100, 300 and 500 mg. It was safe and well tolerated. Placebo lowered the HDL inflammatory index by 28% at 8 hours, while 300 and 500 mg roughly halved it. The index fell in step with the dose swallowed, not with plasma levels, which were low and higher in women.
Single doses in heart patients
Patients with coronary disease or equivalent risk took one fasting dose of 30, 100, 300 or 500 mg of unformulated D-4F or placebo, eight per group; ten more took 500 mg or placebo with a low-fat meal. No safety signal appeared. Peak plasma levels came 30 minutes to 2 hours after the dose, exposure was low and fell with food, the HDL inflammatory index improved at 2 to 4 hours with the two highest doses, and blood lipids did not change.
New HDL particles within 20 minutes
Twenty minutes after apoE-null mice swallowed D-4F, small cholesterol-carrying particles rich in apoA-I and paraoxonase activity appeared in their plasma. HDL turned anti-inflammatory, drew more cholesterol out of macrophages in the dish, and cholesterol moved out of macrophages injected into the mice faster, while most lipoprotein hydroperoxides fell.
With a statin, plaque regressed
Oral D-4F and pravastatin, each at a dose that did nothing alone, together raised HDL cholesterol, apoA-I and paraoxonase in apoE-null mice and made HDL anti-inflammatory. The pair cut lesion area by 79% in young mice and shrank established lesions in old mice over six months. The combination also made HDL anti-inflammatory in monkeys.
Artery relaxation restored
In LDL-receptor-null mice on a Western diet, oral D-4F restored endothelium- and nitric-oxide-dependent artery relaxation and thinned artery walls within two weeks, without changing cholesterol. In mice also lacking apoA-I it still improved relaxation but did not thin the walls, so that effect seemed to need HDL.
Influenza and artery macrophages
In LDL-receptor-null mice infected with influenza A, daily D-4F raised HDL cholesterol and paraoxonase, blunted the rise in LDL and interleukin-6, halved lung virus levels and prevented the surge of macrophages into the aortic arch seen in untreated infected mice.
Less narrowing after balloon injury
D-4F slowed the growth and migration of vascular smooth muscle cells driven by oxidised LDL through heme oxygenase-1, and in rats with balloon-injured carotid arteries it reduced the thickened inner layer and oxidative stress; blocking heme oxygenase-1 weakened both effects.
White matter after stroke
Mice given oral D-4F daily from 2 hours after a permanent stroke had better function at 7 days at one of five doses tested, with more white matter and oligodendrocyte precursors and lower TLR4 and TNF-alpha in the injured brain. Cholesterol, blood-brain-barrier leakage and stroke size did not change; IGF-1 appeared to drive the nerve-fibre growth seen in cultured neurons.
An asthma model
In mice sensitised to ovalbumin, the 4F peptide lowered airway hyperresponsiveness, eosinophil counts, collagen deposits, TGF-beta-1, oxidised-lipid adducts and IgE, and reduced pro-inflammatory HDL, which the authors attributed to lower oxidative stress in the lungs.
Influenza in human lung cells
In a human alveolar type II cell line infected with influenza A, D-4F kept more cells alive, suppressed the virus-driven release of cytokines and the activation of caspases, and stopped the production of pro-inflammatory oxidised phospholipids without changing the release of ordinary phospholipids.
Cholesterol out of macrophages
In mouse macrophages in culture, D-4F increased cholesterol efflux in step with its concentration and time, raised cyclic AMP and the cholesterol exporter ABCA1, and its effect was blocked by a protein kinase A inhibitor.
Macrophages and fibrosis signals
In human monocyte-derived cells pushed toward the alternative, pro-fibrotic state by interleukin-4, D-4F cut that switch by 45% to 60% and lowered TGF-beta-1 mRNA and protein in step with its concentration.
Dosing Data
D-4F is not approved anywhere. These are the oral amounts given in its two phase 1 trials in people with coronary heart disease, as stated in their abstracts. Neither trial tested whether it prevents heart attacks or strokes.
Educational information, not medical advice. Each dose above is tagged with its source: an approved label, a published human study, animal data, or amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
What a Buyer Needs to Know
What is sold, how it is mixed, stored and taken, and what is known about its safety, quality and legal status. Each part names its source. Where we have none, it says unknown.
What is sold
Unknown: we hold no label and no published test that says what forms or vial sizes D-4F is sold in. A vial's own label is a seller's claim, not a source.
Mixing a vial: a worked example
No worked example: none of the doses on this page is a fixed amount in mg or mcg injected under the skin or into a muscle (the routes given are: oral). There is no home-mixing step to show. The reconstitution calculator does the arithmetic for any vial.
Source: the route and amount of each dose row in Dosing Data below.
Storage before and after mixing
Unknown: no label or published stability study on file says how to store D-4F, before or after mixing. The mixing guide sets out the general rules, with their sources: keep a mixed vial in the fridge, and use it promptly, as the bacteriostatic water label says of any drug dissolved in it. The 28 days often quoted is the limit for an opened multiple-dose vial from a manufacturer, an outer limit set for sterility, not a time a mixed solution has been shown to keep. Nobody has published how long D-4F stays intact once mixed.
How it is taken
As it was given in human studies: Oral (Once daily; Study: high-risk coronary patients on statins, 13-day multiple-dose trial).
For injection technique, sites and needle disposal, see the mixing guide.
Source: Used in human trials: the route and frequency of each row in Dosing Data below.
What to expect, and when
How long it stays in the body: not established by a measurement cited on this entry.
How long the doses were given: Study: high-risk coronary patients on statins, 13-day multiple-dose trial: 13 days; Study: coronary heart disease or equivalent risk, single-dose trial: One day.
When effects appear: unknown; no source on this page gives a time to effect for D-4F. Results reported in the studies are under Published Research.
Source: Used in human trials, the duration of each row in Dosing Data below.
Side effects, and when to stop or get help
From the Side Effects section: No significant trend in any safety measure after single doses up to 500 mg (PMID 18323573); Safe and well tolerated over 13 days of daily dosing at 100 to 500 mg (PMID 28795506); No data beyond 13 days, and no study of heart attacks, strokes or plaque in people. Full list and cautions ↓
When to stop or get help: unknown; no label or trial on file sets rules for stopping D-4F. Treat a severe or unexpected reaction as a reason to stop and see a doctor.
Source: the Side Effects section below (“From the two phase 1 trials, which were small and short”).
Interactions
Unknown: a PubMed search for human interaction studies of D-4F (reviewed 2026-10-28) found none. Unknown is not the same as safe to combine.
Every peptide's record, with its source: the interaction matrix.
Checking what you bought
Unknown: no published independent test of D-4F products is in our lab-results database yet, so how products sold under this name measure up is not known.
To read a certificate of analysis, paste it into the COA decoder; it checks the measured mass against D-4F's expected mass, 2,310.6 Da, from this entry's molecular data. Trust & Verification explains what independent testing can and cannot show.
Legal status
US: Research Chemical (Not approved anywhere). Sport: Prohibited (S0 catch-all).
Country by country ↓ · Regulatory tracker
Source: this entry's approval status and the WADA Prohibited List, as in Legal Status below.
Side Effects & Contraindications
Reported Side Effects
From the two phase 1 trials, which were small and short.
Contraindications & Cautions
No product label exists. These cautions follow from the evidence.
Legal Status
D-4F is a research peptide that reached phase 1 trials; it is not approved as a medicine anywhere in the sources read.
Frequently Asked Questions
?What is D-4F?
An 18-amino-acid synthetic peptide that folds like the lipid-binding parts of apolipoprotein A-I, HDL's main protein. It is made from D-amino acids so it survives digestion and can be taken by mouth.
?Does D-4F raise HDL cholesterol?
Not in people. In both phase 1 trials blood lipids did not change. What changed was a laboratory measure of how inflammatory HDL is, which improved for some hours after the higher doses.
?How much of it gets into the blood?
Very little. Plasma levels were low after oral doses and lower with food, yet the HDL effect followed the dose swallowed, which suggests it acts mainly in the gut.
?Has it been shown to prevent heart attacks?
No. Its only human trials lasted one day and 13 days and measured safety, blood levels and HDL function, not heart events or plaque.
?What is the difference between D-4F and L-4F?
They share a sequence but L-4F is built from ordinary L-amino acids, so it must be injected. In heart patients, injected L-4F did not improve HDL function. Its results are not counted here.
?Is D-4F approved anywhere?
No. It has not gone beyond phase 1, and no drug regulator lists it.
References
- [other] PubChem CID 72941823, APP-018 (D-4F): all-D sequence Ac-DWFKAFYDKVAEKFKEAF-NH2, formula C114H156N24O28, molecular weight 2310.6, CAS 452782-06-8. Read October 29, 2026. https://pubchem.ncbi.nlm.nih.gov/compound/72941823
- [clinical-trial] Dunbar RL, et al. "Oral Apolipoprotein A-I Mimetic D-4F Lowers HDL-Inflammatory Index in High-Risk Patients: A First-in-Human Multiple-Dose, Randomized Controlled Trial." Clin Transl Sci, 2017;10(6):455-469. PMID: 28795506.
- [clinical-trial] Bloedon LT, et al. "Safety, pharmacokinetics, and pharmacodynamics of oral apoA-I mimetic peptide D-4F in high-risk cardiovascular patients." J Lipid Res, 2008;49(6):1344-52. PMID: 18323573.
- [pubmed] Navab M, et al. "Oral D-4F causes formation of pre-beta high-density lipoprotein and improves high-density lipoprotein-mediated cholesterol efflux and reverse cholesterol transport from macrophages in apolipoprotein E-null mice." Circulation, 2004;109(25):3215-20. PMID: 15197147.
- [pubmed] Navab M, et al. "D-4F and statins synergize to render HDL antiinflammatory in mice and monkeys and cause lesion regression in old apolipoprotein E-null mice." Arterioscler Thromb Vasc Biol, 2005;25(7):1426-32. PMID: 15845909.
- [pubmed] Ou J, et al. "Effects of D-4F on vasodilation and vessel wall thickness in hypercholesterolemic LDL receptor-null and LDL receptor/apolipoprotein A-I double-knockout mice on Western diet." Circ Res, 2005;97(11):1190-7. PMID: 16224061.
- [pubmed] Van Lenten BJ, et al. "Influenza infection promotes macrophage traffic into arteries of mice that is prevented by D-4F, an apolipoprotein A-I mimetic peptide." Circulation, 2002;106(9):1127-32. PMID: 12196340.
- [pubmed] Liu D, et al. "The apolipoprotein A-I mimetic peptide, D-4F, restrains neointimal formation through heme oxygenase-1 up-regulation." J Cell Mol Med, 2017;21(12):3810-3820. PMID: 28767201.
- [pubmed] Cui X, et al. "D-4F Decreases White Matter Damage After Stroke in Mice." Stroke, 2016;47(1):214-20. PMID: 26604250.
- [pubmed] Nandedkar SD, et al. "D-4F, an apoA-1 mimetic, decreases airway hyperresponsiveness, inflammation, and oxidative stress in a murine model of asthma." J Lipid Res, 2011;52(3):499-508. PMID: 21131532.
- [pubmed] Van Lenten BJ, et al. "D-4F, an apolipoprotein A-I mimetic peptide, inhibits the inflammatory response induced by influenza A infection of human type II pneumocytes." Circulation, 2004;110(20):3252-8. PMID: 15533864.
- [pubmed] Xie Q, et al. "D-4F, an apolipoprotein A-I mimetic peptide, promotes cholesterol efflux from macrophages via ATP-binding cassette transporter A1." Tohoku J Exp Med, 2010;220(3):223-8. PMID: 20208418.
- [pubmed] Song X, et al. "D-4F, an apolipoprotein A-I mimetic, suppresses IL-4 induced macrophage alternative activation and pro-fibrotic TGF-β1 expression." Pharm Biol, 2019;57(1):470-476. PMID: 31335245.
- [review] Navab M, et al. "Apolipoprotein A-I mimetic peptides." Arterioscler Thromb Vasc Biol, 2005;25(7):1325-31. PMID: 15831812.
- [review] Navab M, et al. "Potential clinical utility of high-density lipoprotein-mimetic peptides." Curr Opin Lipidol, 2006;17(4):440-4. PMID: 16832169.
- [pubmed] Navab M, et al. "Intestine may be a major site of action for the apoA-I mimetic peptide 4F whether administered subcutaneously or orally." J Lipid Res, 2011;52(6):1200-1210. PMID: 21444758.
- [pubmed] Morgantini C, et al. "Apolipoprotein A-I mimetic peptides prevent atherosclerosis development and reduce plaque inflammation in a murine model of diabetes." Diabetes, 2010;59(12):3223-8. PMID: 20826564.
- [pubmed] Ning DS, et al. "Apolipoprotein A-I mimetic peptide inhibits atherosclerosis by increasing tetrahydrobiopterin via regulation of GTP-cyclohydrolase 1 and reducing uncoupled endothelial nitric oxide synthase activity." Atherosclerosis, 2021;328:83-91. PMID: 34118596.
- [pubmed] Peterson SJ, et al. "Long-term treatment with the apolipoprotein A1 mimetic peptide increases antioxidants and vascular repair in type I diabetic rats." J Pharmacol Exp Ther, 2007;322(2):514-20. PMID: 17488882.
- [pubmed] Handattu SP, et al. "Oral apolipoprotein A-I mimetic peptide improves cognitive function and reduces amyloid burden in a mouse model of Alzheimer's disease." Neurobiol Dis, 2009;34(3):525-34. PMID: 19344763.
- [clinical-trial] Watson CE, et al. "Treatment of patients with cardiovascular disease with L-4F, an apo-A1 mimetic, did not improve select biomarkers of HDL function." J Lipid Res, 2011;52(2):361-73. PMID: 21068008.
Sources & Citations
Every study on this page was read from its PubMed record on October 29, 2026. Identity data come from PubChem (CID 72941823); regulatory status from Drugs@FDA (openFDA) and the EMA medicines list. Grey Peptides sells nothing and links to no vendor.
Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Talk to a licensed clinician about your own situation.