ALC-0315

ALC-0315 ([(4-hydroxybutyl)azanediyl]di(hexane-6,1-diyl) bis(2-hexyldecanoate)) is a synthetic lipid. A colorless oily material, it has attracted attention as a component of the SARS-CoV-2 vaccine, BNT162b2, from BioNTech and Pfizer. 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.[1][2] These nanoparticles promote the uptake of therapeutically effective nucleic acids such as oligonucleotides or mRNA both in vitro and in vivo.[3][4]

ALC-0315
ALC-0315 Struktur.svg
Names
Preferred IUPAC name
[(4-Hydroxybutyl)azanediyl]di(hexane-6,1-diyl) bis(2-hexyldecanoate)
Identifiers
  • 2036272-55-4 checkY
3D model (JSmol)
ChemSpider
UNII
  • InChI=1S/C48H95NO5/c1-5-9-13-17-19-27-37-45(35-25-15-11-7-3)47(51)53-43-33-23-21-29-39-49(41-31-32-42-50)40-30-22-24-34-44-54-48(52)46(36-26-16-12-8-4)38-28-20-18-14-10-6-2/h45-46,50H,5-44H2,1-4H3
    Key: QGWBEETXHOVFQS-UHFFFAOYSA-N
  • CCCCCCCCC(CCCCCC)C(=O)OCCCCCCN(CCCCO)CCCCCCOC(=O)C(CCCCCC)CCCCCCCC
Properties
C48H95NO5
Molar mass 766.290 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

At physiological pH, ALC-0315 becomes protonated at the nitrogen atom, yielding an ammonium cation that is attracted to the messenger RNA (mRNA), which is anionic.[5]

SynthesisEdit

The preparation of ALC-0315 was first described in a patent application to lipid nanoparticles by Acuitas Therapeutics in 2017.[6]:137 The final step is a reductive amination reaction in which 4-aminobutanol is condensed with a lipid aldehyde, using sodium triacetoxyborohydride as the reducing agent to convert the intermediate imines to the amine of the product.

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

UseEdit

ALC-0315 is one of the components of the BNT162b2 vaccine. Its chemical properties as a tertiary amine mean that its cation can form an electrostatic bond to the messenger RNA which carries the genetic information for the SARS-CoV-2 spike protein formation in the human body.[5] Importantly, once the lipid nanoparticle which encapsulates the mRNA has been absorbed into muscle cells (a process called receptor-mediated endocytosis) the more acidic environment within the endosome fully protonates the ALC-0315 and as a result the nanoparticle releases its payload of mRNA.[2]

See alsoEdit

ReferencesEdit

  1. ^ Michael McCoy (February 12, 2021). "Lipids, the unsung COVID-19 vaccine component, Get Investment". Chemical and Engineering News.
  2. ^ a b Ryan Cross (2021). "Without These Lipid Shells, There Would Be No mRNA Vaccines for COVID-19". Chemical & Engineering News: 16–19. doi:10.47287/cen-09908-feature1.
  3. ^ mRNA-based therapeutics — developing a new class of drugs, Ugur Sahin, Katalin Karikó and Özlem Türeci, Nature Reviews Drug Discovery, 13, 759-780 (2014), doi:10.1038/nrd4278.
  4. ^ mRNA vaccines — a new era in vaccinology, Norbert Pardi, Michael J. Hogan, Frederick W. Porter and Drew Weissman, Nature Reviews Drug Discovery, 17, 261-279 (2018), doi:10.1038/nrd.2017.243.
  5. ^ a b Medicines and Healthcare products Regulatory Agency (11 December 2020). "Public Assessment Report: Authorisation for Temporary Supply COVID-19 mRNA Vaccine BNT162b2" (PDF).
  6. ^ WO application 2018081480, Ansell S.; Barbosa C. & Du X. et al., "Lipid nanoparticle formulations", published 2018-05-03, assigned to Acuitas Therapeutics, Inc.