ALC-0315 ( 4-hydroxybutyl)azanediyli(hexane-6,1-diyl) bis(2-hexyldecanoate)) is a synthetic

lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids incl ...

. A colorless oily material, it has attracted attention as a component of the

SARS-CoV-2 vaccine A COVID19 vaccine is a vaccine intended to provide acquired immunity against severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), the virus that causes coronavirus disease 2019 (COVID19). Prior to the COVID19 pandemic, an es ...

, BNT162b2, from

BioNTech BioNTech SE ( ; or short for Biopharmaceutical New Technologies) is a German biotechnology company based in Mainz that develops and manufactures active immunotherapies for patient-specific approaches to the treatment of diseases. It develops ...

and

Pfizer Pfizer Inc. ( ) is an American multinational pharmaceutical and biotechnology corporation headquartered on 42nd Street in Manhattan, New York City. The company was established in 1849 in New York by two German entrepreneurs, Charles Pfize ...

. Specifically, it is one of four components that form lipid nanoparticles (LNPs), which encapsulate and protect the otherwise fragile mRNA that is the active ingredient in these drugs. These nanoparticles promote the uptake of therapeutically effective

nucleic acid Nucleic acids are biopolymers, macromolecules, essential to all known forms of life. They are composed of nucleotides, which are the monomers made of three components: a 5-carbon sugar, a phosphate group and a nitrogenous base. The two main ...

s such as

oligonucleotide Oligonucleotides are short DNA or RNA molecules, oligomers, that have a wide range of applications in genetic testing, research, and forensics. Commonly made in the laboratory by solid-phase chemical synthesis, these small bits of nucleic acids ...

s or mRNA both ''

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology and ...

'' and ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...

''. Below physiological pH, ALC-0315 becomes

protonated In chemistry, protonation (or hydronation) is the adding of a proton (or hydron, or hydrogen cation), (H+) to an atom, molecule, or ion, forming a conjugate acid. (The complementary process, when a proton is removed from a Brønsted–Lowry acid ...

at the nitrogen atom, yielding an

ammonium The ammonium cation is a positively-charged polyatomic ion with the chemical formula or . It is formed by the protonation of ammonia (). Ammonium is also a general name for positively charged or protonated substituted amines and quaternar ...

cation An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...

that is attracted to the messenger RNA (mRNA), which is

anion An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by conve ...

ic.

Synthesis

The preparation of ALC-0315 was first described in a patent application to lipid nanoparticles by Acuitas Therapeutics in 2017. The final step is a reductive amination reaction in which 4-aminobutanol is condensed with a lipid

aldehyde In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl group ...

, using sodium triacetoxyborohydride as the reducing agent to convert the intermediate

imines In organic chemistry, an imine ( or ) is a functional group or organic compound containing a carbon–nitrogen double bond (). The nitrogen atom can be attached to a hydrogen or an organic group (R). The carbon atom has two additional single bon ...

to the

amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent su ...

of the product. :2 (C₈H₁₇)(C₆H₁₃)CHCO₂(CH₂)₅CHO + H₂N(CH₂)₄OH + 2 NaBH(O₂CCH₃)₃ → ALC-0315

Use

ALC-0315 is one of the components of the BNT162b2 vaccine (0.43 mg per dose). Its chemical properties as a

tertiary amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent such ...

mean that its

can form an

ionic bond Ionic bonding is a type of chemical bonding that involves the electrostatic attraction between oppositely charged ions, or between two atoms with sharply different electronegativities, and is the primary interaction occurring in ionic compoun ...

to the messenger RNA which carries the genetic information for the

SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a No ...

spike protein In virology, a spike protein or peplomer protein is a protein that forms a large structure known as a spike or peplomer projecting from the surface of an enveloped virus. as cited in The proteins are usually glycoproteins that form dimers o ...

formation in the human body. Importantly, once the lipid nanoparticle which encapsulates the mRNA has been absorbed into antigen-presenting cells (a process called receptor-mediated endocytosis) the more acidic environment within the

endosome Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membrane c ...

fully protonates the ALC-0315 as a result the nanoparticle releases its payload of mRNA. In December 2021 there were objections raised against the use of ALC-0315 and ALC-0159 (and some other solid lipid nanoparticles) in humans by critics of mRNA-COVID-19 vaccines in Germany but the German pharmaceutical trade journal ''Pharmazeutische Zeitung'' ( de) and the German investigative collective Correctiv refuted this and stated as one important reason that the European Medicines Agency has approved the vaccine and this includes all its ingredients.

References

{{reflist Esters Amines Lipids Primary alcohols

Synthesis

Use

See also

References