Deulinoleate ethyl (also known as di-deuterated ethyl linoleate, di-deuterated linoleic acid ethyl ester, 11,11-''d''-ethyl linoleate, or ethyl 11,11-''d''-linoleate) is an experimental, orally-bioavailable synthetic
deuterated polyunsaturated fatty acid
In biochemistry and nutrition, a polyunsaturated fat is a fat that contains a polyunsaturated fatty acid (abbreviated PUFA), which is a subclass of fatty acid characterized by a backbone with two or more carbon–carbon double bonds.
Some polyunsa ...
(PUFA), a part of
reinforced lipids
Reinforced lipids are lipid molecules in which some of the fatty acids contain deuterium. They can be used for the protection of living cells by slowing the chain reaction due to isotope effect on lipid peroxidation. The lipid bilayer of the cel ...
. It is an
isotopologue
In chemistry, isotopologues (also spelled isotopologs) are molecules that differ only in their isotopic composition. They have the same chemical formula and bonding arrangement of atoms, but at least one atom has a different number of neutrons t ...
of
linoleic acid
Linoleic acid (LA) is an organic compound with the formula . Both alkene groups () are ''cis''. It is a fatty acid sometimes denoted 18:2 (n−6) or 18:2 ''cis''-9,12. A linoleate is a salt or ester of this acid.
Linoleic acid is a polyunsat ...
, an
essential omega-6
Omega−6 fatty acids (also referred to as ω−6 fatty acids or ''n''−6 fatty acids) are a family of polyunsaturated fatty acids (PUFA) that share a final carbon-carbon double bond in the ''n''−6 position, that is, the sixth bond, count ...
PUFA. The deuterated compound, while identical to natural linoleic acid except for the presence of deuterium, is resistant to
lipid peroxidation
Lipid peroxidation, or lipid oxidation, is a complex chemical process that leads to oxidative degradation of lipids, resulting in the formation of peroxide and hydroperoxide derivatives.{{Cite journal , last1=Ayala , first1=Antonio , last2=Muñoz ...
which makes studies of its
cell-protective properties worthwhile.
Mechanism of action
Deulinoleate ethyl is recognized by cells as identical to normal linoleic acid. But when taken up, it is converted into 13,13-''d''-arachidonic acid, a heavy isotope version of
arachidonic acid
Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega−6 fatty acid 20:4(ω−6), or 20:4(5,8,11,14). It is a precursor in the formation of leukotrienes, prostaglandins, and thromboxanes.
Together with omega−3 fatty acids an ...
, that gets incorporated into lipid membranes. The deuterated compound resists the non-enzymatic
lipid peroxidation
Lipid peroxidation, or lipid oxidation, is a complex chemical process that leads to oxidative degradation of lipids, resulting in the formation of peroxide and hydroperoxide derivatives.{{Cite journal , last1=Ayala , first1=Antonio , last2=Muñoz ...
(LPO) through
isotope effect — a non-antioxidant based mechanism that protects mitochondrial, neuronal and other lipid membranes, thereby greatly reducing the levels of numerous LPO-derived toxic products such as
reactive carbonyls.
Deulinoleate ethyl inhibits ferroptosis by stopping the autoxidation process through the kinetic isotope effect. The protective effect of D-PUFAs was verified in erastin- and RSL3-induced ferroptosis models, with demonstrated efficacy in various disease models, particularly neurodegenerative disorders and clinical trials of deulinoleate ethyl begun in 2018.
Clinical development
Friedreich's ataxia
A double-blind
comparator-controlled Phase I/II clinical trial for
Friedreich's ataxia
Friedreich's ataxia (FRDA) is a rare, inherited, autosomal recessive neurodegenerative disorder that primarily affects the nervous system, causing progressive damage to the spinal cord, peripheral nerves, and cerebellum, leading to impaired ...
, sponsored by
Retrotope
Retrotope, Inc. is a drug development company advancing the idea that polyunsaturated fatty acids (PUFA) drugs fortified with heavy isotopes (reinforced lipids) protect living cells by making bonds within the delicate molecules inside and around ...
and
Friedreich's Ataxia Research Alliance, was conducted to determine the safety profile and appropriate dosing for consequent trials. Deulinoleate ethyl was promptly absorbed and was found to be safe and tolerable over 28 days at the maximal dose of 9 g/day. It improved
peak workload and
peak oxygen consumption in the test group compared to the control group who received the equal doses of normal, non-deuterated ethyl linoleate. Another randomized, double-blind, placebo-controlled clinical study began in 2019.
Infantile neuroaxonal dystrophy
An open-label clinical study for
infantile neuroaxonal dystrophy
Infantile neuroaxonal dystrophy (INAD) is a rare pervasive developmental disorder that primarily affects the nervous system. Individuals with infantile neuroaxonal dystrophy typically do not have any symptoms at birth, but between the ages of abo ...
evaluating long-term evaluation of efficacy, safety, tolerability, and pharmacokinetics of deulinoleate ethyl, which, when taken with food, can protect the neuronal cells from degeneration, started in the Summer 2018.
Phospholipase 2G6-associated neurodegeneration
In 2017, the
FDA
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
granted deulinoleate ethyl
orphan drug
An orphan drug is a medication, pharmaceutical agent that is developed to treat certain rare medical conditions. An orphan drug would not be profitable to produce without government assistance, due to the small population of patients affected by th ...
designation in the treatment of
phospholipase 2G6-associated neurodegeneration (
PLAN
A plan is typically any diagram or list of steps with details of timing and resources, used to achieve an Goal, objective to do something. It is commonly understood as a modal logic, temporal set (mathematics), set of intended actions through wh ...
).
Amyotrophic lateral sclerosis
In 2018, deulinoleate ethyl was given to a patient with
amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or—in the United States—Lou Gehrig's disease (LGD), is a rare, Terminal illness, terminal neurodegenerative disease, neurodegenerative disorder that results i ...
(ALS) under a "compassionate use scheme".
Progressive supranuclear palsy
In 2020, the FDA granted orphan drug designation deulinoleate ethyl for the treatment of patients with
progressive supranuclear palsy
Progressive supranuclear palsy (PSP) is a late-onset neurodegenerative disease involving the gradual deterioration and death of specific volumes of the brain, linked to 4-repeat tau pathology. The condition leads to symptoms including Balance di ...
(PSP). PSP is a disease involving modification and dysfunction of tau protein; mechanism of action of deulinoleate ethyl both lowers lipid peroxidation and prevents mitochondrial cell death of neurons which is associated with disease onset and progression.
Preclinical research
Alzheimer's disease
Deulinoleate ethyl has been shown to be effective in a model of
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
in mice.
References
{{Reflist
Biochemistry
Ethyl esters
Fatty acid esters
Deuterated compounds