N-Acetylated-L-arginine (NALA) is an enhanced protein aggregation suppressor under interfacial stresses and elevated temperature for protein liquid formulations.

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  • Author(s): Kim NA;Kim NA; Hada S; Hada S; Jeong SH; Jeong SH
  • Source:
    International journal of biological macromolecules [Int J Biol Macromol] 2021 Jan 01; Vol. 166, pp. 654-664. Date of Electronic Publication: 2020 Oct 31.
  • Publication Type:
    Journal Article
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: Netherlands NLM ID: 7909578 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0003 (Electronic) Linking ISSN: 01418130 NLM ISO Abbreviation: Int J Biol Macromol Subsets: MEDLINE
    • Publication Information:
      Publication: Amsterdam : Elsevier
      Original Publication: Guildford, Eng., IPC Science and Technology Press.
    • Subject Terms:
      Temperature*; Arginine/*analogs & derivatives ; Protein Aggregates/*drug effects ; Proteins/*chemistry; Arginine/pharmacology ; Buffers ; Calorimetry, Differential Scanning ; Chromatography, Gel ; Circular Dichroism ; Colloids/chemistry ; Glycine/chemistry ; Hydrogen-Ion Concentration ; Immunoglobulin G/chemistry ; Immunoglobulins, Intravenous ; Particle Size ; Protein Conformation
    • Abstract:
      Even though arginine hydrochloride has been recognized as a protein aggregation suppressor in the biopharmaceutical industry, its use has been questioned due to decreasing transition unfolding temperatures (T m ). Four compounds were designed to enhance the role of arginine by changing the length of the carbon chain with removal or N-acetylation of α-amino group. Biophysical properties were observed by differential scanning calorimetry (DSC), dynamic light scattering (DLS), size-exclusion chromatography (SEC), and flow imaging (FI). N-Acetyl-L-arginine (NALA) performed the best at minimizing decrease in T m with arginine at different pH. NALA also demonstrated relatively higher colloidal stability than arginine hydrochloride, especially in the acidic pH, thereby reducing agitation stress of IgG. Moreover, NALA exhibited a cooperative effect with commercially used glycine buffer for IVIG to maintain the monomer contents with almost no change and suppressed larger particle formation after agitation with heat. The study concludes that the decreasing T m of proteins by arginine hydrochloride is due to amide group in the α-carbon chain. Moreover, chemical modification on the group compared to removing it will be a breakthrough of arginine's limitations and optimize storage stability of protein therapeutics.
      Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
      (Copyright © 2020 Elsevier B.V. All rights reserved.)
    • Contributed Indexing:
      Keywords: Arginine hydrochloride; DSC; N-Acetyl-L-arginine; Protein aggregation; Protein formulation
    • Accession Number:
      0 (Buffers)
      0 (Colloids)
      0 (Immunoglobulin G)
      0 (Immunoglobulins, Intravenous)
      0 (Protein Aggregates)
      0 (Proteins)
      94ZLA3W45F (Arginine)
      TE7660XO1C (Glycine)
      TQ7DL04CAE (N-acetyl-L-arginine)
    • Publication Date:
      Date Created: 20201102 Date Completed: 20210407 Latest Revision: 20210407
    • Publication Date:
      20240829
    • Accession Number:
      10.1016/j.ijbiomac.2020.10.223
    • Accession Number:
      33137385