Synthesis of Mandarin Fish Ranavirus (MFRV) - viral insulin/IGF-like peptide — ASN Events
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  3. Synthesis of Mandarin Fish Ranavirus (MFRV) - viral insulin/IGF-like peptide

Synthesis of Mandarin Fish Ranavirus (MFRV) - viral insulin/IGF-like peptide (#290)

Marta Lubos 1 , Jiří Jiráček 1
  1. Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic

Insulin, together with two insulin-like growth factors (IGF-1 and IGF-2), belongs to a superfamily of structurally related peptide hormones1. The insulin/IGF system regulates cell metabolism, proliferation, and differentiation, among other physiological processes. Insulin, IGF-1 and IGF-2 bind to a different but highly homologous in structure and mechanism of action receptors – the insulin receptor (IR) and the IGF-1 receptor (IGF-1R), which are both members of receptor tyrosine kinase (RTK) family2,3. Although significant efforts have been made to understand the insulin/IGF system, the existence of viral insulin/IGF-1-like peptides (VILPs) and their impact on mammalian cells were unknown until recently4. Noteworthy, VILPs have up to 50% sequence homology to human insulin and IGF-1, and contain all crucial cysteine residues4,5.

In this study, we focused on the total chemical synthesis of Mandarin Fish Ranavirus VILP (MFRV VILP). Both single-chain (sc) and double-chain (dc) forms of MFRV were synthesized and characterized. Double-chain MFRV (dcMFRV) is composed of A chain (24 residues) and B chain (30 residues) which are connect by two inter-chain disulfide bonds and one intra-A-chain linkage. Whereas single-chain MFRV (scMFRV) consists of 64 residues and contains three intra-chain disulfide bonds (see below). Following Fmoc-based solid phase peptide synthesis, each disulfide bond was formed stepwise using orthogonal cysteine protecting groups6. We will present methodology details of the challenging scMFRV and dcMFRV VILP syntheses altogether with analytical data of the products.

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  1. S.J. Chan, S. Nagamatsu, Q.P. Cao, D.F. Steiner, Structure and evolution of insulin and insulin-like growth factors in chordates, Prog. Brain Res., 1992, 92, 15-24.
  2. M. Annunziata, R. Granata, E. Ghigo, The IGF system, Acta Diabetol., 2011, 48, 1-9.
  3. A. Denley, L.J. Cosgrove, G.W. Booker, J.C. Wallace, B.E. Forbes, Molecular interactions of the IGF system, Cytokine Growth Factor Rev., 2005, 16, 421-439.
  4. E. Altindis, W. Cai, M. Sakaguchi, F. Zhang, W. GuoXiao, F. Liu, P. De Meyts, V. Gelfanov, H. Pan, R. DiMarchi, C.R. Kahn, Viral insulin-like peptides activate human insulin and IGF-1 receptor signaling: A paradigm shift for host-microbe interactions, Proc. Natl. Acad. Sci. U.S.A., 2018, 115, 2461-2466.
  5. M. Chrudinová, F. Moreau, H.L. Noh, T. Páníková, L. Žáková, R.H. Friedline, F.A. Valenzuela, J.K. Kim, J. Jiráček, C.R. Kahn, E. Altindis, Characterization of viral insulins reveals white adipose tissue specific effects in mice, Mol. Metab., 2021, 44, 101121.
  6. F. Liu, E.Y. Luo, D.B. Flora, A.R. Mezo, A synthetic route to human insulin using isoacyl peptides, Angew. Chem. Int. Ed., 2014, 53, 3983-3987.
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