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Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Research Article

Prothymosin α and its C-Terminal Immunoreactive Decapeptide Show No Evidence of Acute Toxicity: A Preliminary In Silico, In Vitro and In Vivo Investigation

Author(s): Anastasios I. Birmpilis*, Panagiotis Vitsos*, Ioannis V. Kostopoulos, Lillian Williams, Kyriaki Ioannou, Pinelopi Samara, Chrysoula-Evangelia Karachaliou, Ioannis F. Voutsas, Elena Alyfanti, Nikolaos Angelis, Nikolaos G. Gavalas, Themis Gkraikou, Niki Kappa, Eleftheria Klagkou, Persefoni Klimentzou, Spiridoula Nikou, Nikos E. Papaioannou, Margarita Skopeliti, David Toukli, Meletios-Athanasios Dimopoulos, Aristotelis Bamias, Evangelia Livaniou, Hubert Kalbacher, Ourania E. Tsitsilonis* and Wolfgang Voelter

Volume 29, Issue 42, 2022

Published on: 14 January, 2022

Page: [6463 - 6478] Pages: 16

DOI: 10.2174/0929867328666211117093401

Price: $65

Abstract

Background: Members of the α-thymosin family have long been studied for their immunostimulating properties. Among them, the danger-associated molecular patterns (DAMPs) prothymosin α (proTα) and its C-terminal decapeptide proTα(100–109) have been shown to act as immunomodulators in vitro, due to their ability to promote T helper type 1 (Th1) responses. Recently, we verified these findings in vivo, showing that both proTα and proTα(100-109) enhance antitumor-reactive T cell-mediated responses.

Methods: In view of the eventual use of proTα and proTα(100-109) in humans, we investigated their safety profile in silico, in human leukocytes and cancer cell lines in vitro, and in immunocompetent mice in vivo, in comparison to the proTα derivative thymosin alpha 1 (Τα1), a 28-mer peptide extensively studied for its safety in clinical trials.

Results: In silico prediction via computational tools showed that all three peptide sequences likely are non-toxic or do not induce allergic regions. In vitro, pro- Tα, proTα(100-109) and Tα1 did not affect the viability of human cancer cell lines and healthy donor-derived leukocytes, did not promote apoptosis or alter cell cycle distribution. Furthermore, mice injected with proTα, proTα(100-109) and Tα1 at doses equivalent to the suggested dose regimen of Tα1 in humans, did not show signs of acute toxicity, whereas proTα and proTα(100-109) increased the levels of proinflammatory and Th1- type cytokines in their peripheral blood.

Conclusion: Our preliminary findings suggest that proTα and proTα(100-109), even at high concentrations, are non-toxic in vitro and in an acute toxicity model in vivo; moreover, we show that the two peptides retain their immunomodulatory properties in vivo and, eventually, could be considered for therapeutic use in humans.

Keywords: DAMP, prothymosin alpha, in vivo toxicity, immunomodulation, thymic peptides, thymosin alpha 1.

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