Antifreeze glycopeptides: from structure and activity studies to current approaches in chemical synthesis

Abstract

Antifreeze glycopeptides (AFGPs) are a class of biological antifreeze agents found predominantly in Arctic and Antarctic species of fish. They possess the ability to regulate ice nucleation and ice crystal growth, thus creating viable life conditions at temperatures below the freezing point of body fluids. AFGPs usually consist of 4-55 repetitions of the tripeptide unit Ala-Ala-Thr that is O-glycosylated at the threonine side chains with β-D-galactosyl-(1 → 3)-α-N-acetyl-D-galactosamine. Due to their interesting properties and high antifreeze activity, they have many potential applications, e.g., in food industry and medicine. Current research is focused towards understanding the relationship between the structural preferences and the activity of the AFGPs, as well as developing time and cost efficient ways of synthesis of this class of molecules. Recent computational studies in conjunction with experimental results from NMR and THz spectroscopies were a possible breakthrough in understanding the mechanism of action of AFGPs. At the moment, as a result of these findings, the focus of research is shifted towards the analysis of behaviour of the hydration shell around AFGPs and the impact of water-dynamics retardation caused by AFGPs on ice crystal growth. In the field of organic synthesis of AFGP analogues, most of the novel protocols are centered around solid-phase peptide synthesis and multiple efforts are made to optimize this approach. In this review, we present the current state of knowledge regarding the structure and activity of AFGPs, as well as approaches to organic synthesis of these molecules with focus on the most recent developments.

Keywords: AFGP; Antifreeze glycopeptides; Hydration shell dynamics; Solid-phase peptide synthesis; Structure–activity relationship; Terahertz spectroscopy.

Fig. 1

Structure of a natural AFGP (n = 4–55)

Fig. 2

Thermal hysteresis gap is the result of the Kelvin effect caused by the introduction of AFGPs to the solution

Fig. 3

Hypothetical mechanisms of AFGP ice growth inhibition: the step-pinning model (a) and the mattress model (b)

Fig. 4

Hypothetical possibilities for the formation of hydrogen bonds between the AFGPs and the ice crystal lattice

Fig. 5

Synthesis of the protected T-antigen building block for SPPS published by Nagel et al. (2011)

Fig. 6

General overview of the SPPS approach for the synthesis of AFGPs; n = 1–5 (Izumi et al. 2013)

Fig. 7

AFGP analogues synthesized by different research groups