Improving solid-phase peptide synthesis with Vapourtec


    Here we present our latest application note, Automated continuous flow solid-phase peptide synthesis (CF-SPPS) and evaluation of GLP-1. In this work, the Variable Bed Flow Reactor was used to evaluate the effect of different solid media in the synthesis of the 30-mer Glucagon-Like Peptide 1 (GLP-1) as an example peptide.

    Solid-phase peptide synthesis and the need to shift into flow

    Solid-phase peptide synthesis (SPPS), traditionally undertaken using batch techniques, has allowed scientists to synthesise a variety of peptides. Unfortunately, batch techniques require large excesses of reagents and solvent and are further limited due to the lack of real-time reaction monitoring.

    To address these issues, continuous flow (CF)-SPPS has already been explored, improving peptide purity compared to traditional batch routes [1]. In its simplest form, this can be achieved by flowing reagents through a fixed bed reactor packed with the solid media support (resin beads).  This approach achieves some benefits over batch reactors by improving interaction between reagents and resin beads.

    Recently, the Pentelute Lab from the MIT published in Science the synthesis of a collection of peptides they assembled in continuous flow using a bespoke system [2]. One of these peptides, GLP-1, was afforded with a crude purity of 70%.

    Variable Bed Flow Reactor, the next level of CF-SPPS

    When using traditional fixed bed flow reactors, keeping the packing density of the solid support media constant through the synthesis is challenging. To overcome this problem, Vapourtec developed a new reactor concept, a Variable Bed Flow Reactor (VBFR) designed to both control and monitor the packing density of the solid support. By using the VBFR in CF-SPPS a number of key benefits are realized:

    • Consistent packing density
    • Reactor volume kept to a minimum
    • Providing real-time data never seen before in peptide synthesis [3,4].

    The Vapourtec RS-400 flow chemistry system can be configured to perform CF-SPPS when equipped with a VBFR. Thanks to the wide range of available in-line detection systems (i.e. Raman, FTIR, UV-Vis spectroscopy), our Vapourtec systems can offer better insight into the reaction progress and ultimately providing higher purity peptides.

    Glucagon-like peptide 1, a benchmark of pharmaceutical interest

    GLP-1 is a 30-mer metabolic hormone which plays a key role regulating sugar levels in the body. Drugs based on GLP-1 are used to treat type-2 diabetes, with associated benefits such as weight loss, lower risk of hypoglycaemia, just to name a few. With a broad pharmacological interest, there is a market need for a peptide synthesiser that can synthesise GLP-1 and similar peptides with high purity and yield.

    In this application note, different solid support media were evaluated using the synthesis of GLP-1. Dr Manuel Nuño commented “In this application note, we report the synthesis of GLP-1 with a purity of up to 82 % in just under 5 hours. This high yield- high purity synthesis was only possible thanks to the VBFR. The use of the VBFR in CF-SPPS will allow scientists to better understand the challenges of their peptide sequences and, react to events otherwise unseen. The VBFR will certainly allow chemists to pinpoint challenging couplings, evaluate different chemical approaches, and assist scale up processes”.


    [1] Gordon, C. P. The renascence of continuous-flow peptide synthesis – an abridged account of solid and solution-based approaches. Org. Biomol. Chem. 16, 180–196 (2018).

    [2] Hartrampf, N. et al. Synthesis of proteins by automated flow chemistry. Science (80-. ). 368, 980 LP – 987 (2020).

    [3] Sletten, E. T., Danglad-Flores, J., Nuño, M., Guthrie, D. & Seeberger, P. H. Automated Glycan Assembly in a Variable-Bed Flow Reactor Provides Insights into Oligosaccharide–Resin Interactions. (2020)

    [4] Sletten, E. T., Nuño, M., Guthrie, D. & Seeberger, P. H. Real-time monitoring of solid-phase peptide synthesis using a variable bed flow reactor. Chem. Commun. (2019)

    Flow and batch SPPS is fundamentally different, this brief animation explains how. Click here

    To read this application note click here

    To find out more about Vapourtec’s Variable Bed Flow Reactor click here

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