ALC-0315

ALC-0315
Names
Preferred IUPAC name
[(4-Hydroxybutyl)azanediyl]di(hexane-6,1-diyl) bis(2-hexyldecanoate)
Identifiers
CAS Number
3D model (JSmol)
ChemSpider
PubChem CID
UNII
InChI
  • 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
SMILES
  • CCCCCCCCC(CCCCCC)C(=O)OCCCCCCN(CCCCO)CCCCCCOC(=O)C(CCCCCC)CCCCCCCC
Properties
Chemical formula
 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

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]

Below 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]

Synthesis

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

Use

ALC-0315 is one of the components of the BNT162b2 vaccine (0.43 mg per dose).[7] Its chemical properties as a tertiary amine mean that its cation can form an ionic 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 antigen-presenting cells (a process called receptor-mediated endocytosis) the more acidic environment within the endosome fully protonates the ALC-0315 as a result the nanoparticle releases its payload of mRNA.[2][8] 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.[9][10]

See also

Pfizer–BioNTech COVID-19 vaccine nanoparticle ingredients

References

  1. ↑ Michael McCoy (February 12, 2021). "Lipids, the unsung COVID-19 vaccine component, Get Investment". Chemical and Engineering News.
  2. 1 2 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. 1 2 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.
  7. ↑ Schoenmaker, Linde; Witzigmann, Dominik; Kulkarni, Jayesh A.; Verbeke, Rein; Kersten, Gideon; Jiskoot, Wim; Crommelin, Daan J. A. (2021-05-15). "mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability". International Journal of Pharmaceutics. 601: 120586. doi:10.1016/j.ijpharm.2021.120586. ISSN 0378-5173.
  8. ↑ Chaudhary, Namit; Weissman, Drew; Whitehead, Kathryn A. (2021). "MRNA vaccines for infectious diseases: Principles, delivery and clinical translation". Nature Reviews Drug Discovery. 20 (11): 817–838. doi:10.1038/s41573-021-00283-5. PMC 8386155. PMID 34433919.
  9. ↑ "Absurde Diskussion um Lipide ALC-0315 und ALC-0159". 18 January 2022. Retrieved 23 January 2022. Erstens stimmt es nicht, dass die Zusatzstoffe unerlaubt sind. Denn Comirnaty ist zugelassen und damit sind auch alle darin enthaltenen Hilfsstoffe zugelassen. [Firstly, it is not true that the additives are illegal. Because Comirnaty is approved and therefore all the additives contained in it are also approved.]
  10. ↑ "Faktencheck: Nein, der Biontech-Impfstoff enthält keine Inhaltsstoffe, die nicht für Menschen zugelassen sind". 23 December 2021. Retrieved 23 January 2022. Doch anders als behauptet, sind sie nicht gesundheitsschädlich, die EMA hat die Impfung und somit auch deren Bestandteile zugelassen. Dass die Bestandteile bei der Zulassung der mRNA-Impfstoffe geprüft wurden, bestätigte uns auch das Paul-Ehrlich-Institut (PEI) auf Anfrage. [But contrary to what is claimed, they are not harmful to health, the EMA has approved the vaccination and thus also its components. On request, the Paul Ehrlich Institute (PEI) also confirmed that the components were tested when the mRNA vaccines were approved.]
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