PASylated Thymosin α1: A Long-Acting Immunostimulatory Peptide for Applications in Oncology and Virology

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2020 Dec 30

PMID 33374407

Citations 7

Authors

Uli Binder

Arne Skerra

Affiliations

Soon will be listed here.

Abstract

Thymosin α1 (Tα1) is an immunostimulatory peptide for the treatment of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections and used as an immune enhancer, which also offers prospects in the context of COVID-19 infections and cancer. Manufacturing of this N-terminally acetylated 28-residue peptide is demanding, and its short plasma half-life limits in vivo efficacy and requires frequent dosing. Here, we combined the PASylation technology with enzymatic in situ N-acetylation by RimJ to produce a long-acting version of Tα1 in at high yield. ESI-MS analysis of the purified fusion protein indicated the expected composition without any signs of proteolysis. SEC analysis revealed a 10-fold expanded hydrodynamic volume resulting from the fusion with a conformationally disordered Pro/Ala/Ser (PAS) polypeptide of 600 residues. This size effect led to a plasma half-life in rats extended by more than a factor 8 compared to the original synthetic peptide due to retarded kidney filtration. Our study provides the basis for therapeutic development of a next generation thymosin α1 with prolonged circulation. Generally, the strategy of producing an N-terminally protected PASylated peptide solves three major problems of peptide drugs: (i) instability in the expression host, (ii) rapid degradation by serum exopeptidases, and (iii) low bioactivity because of fast renal clearance.

Citing Articles

Phenotypic drug discovery: a case for thymosin alpha-1.

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The use of alpha 1 thymosin as an immunomodulator of the response against SARS-Cov2.

Espinar-Buitrago M, Tarancon-Diez L, Vazquez-Alejo E, Magro-Lopez E, Genebat M, Romero-Candau F Immun Ageing. 2023; 20(1):32.

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PASylated Urate Oxidase Enzyme: Enhancing Biocatalytic Activity, Physicochemical Properties, and Plasma Half-Life.

Najjari A, Shahbazmohammadi H, Nojoumi S, Omidinia E ACS Omega. 2022; 7(50):46118-46130.

PMID: 36570261 PMC: 9773812. DOI: 10.1021/acsomega.2c04071.

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