A Rapid and Efficient Building Block Approach for Click Cyclization of Peptoids.

Mai Shamir,Mattan Hurevich,Mamidi Samarasimhareddy,Assaf Friedler,Deborah E. Shalev

doi:10.3389/fchem.2020.00405

Abstract

Cyclic peptide-peptoid hybrids possess improved stability and selectivity over linear peptides and are thus better drug candidates. However, their synthesis is far from trivial and is usually difficult to automate. Here we describe a new rapid and efficient approach for the synthesis of click-based cyclic peptide-peptoid hybrids. Our methodology is based on a combination between easily synthesized building blocks, automated microwave assisted solid phase synthesis and bioorthogonal click cyclization. We proved the concept of this method using the INS peptide, which we have previously shown to activate the HIV-1 integrase enzyme. This strategy enabled the rapid synthesis and biophysical evaluation of a library of cyclic peptide-peptoid hybrids derived from HIV-1 integrase in high yield and purity. The new cyclic hybrids showed improved biological activity and were significantly more stable than the original linear INS peptide.

Highlights

Linear peptides have several disadvantages as drug leads, such as metabolic instability due to enzymatic degradation, hydrolysis or oxidation, short half-life and rapid clearance, poor oral bioavailability and in some cases poor solubility and low membrane permeability (Marqus et al, 2017)
To synthesize a diverse library of cyclic peptide-peptoids hybrids, there was a need for the corresponding peptoid building blocks that would be incorporated into the peptide sequence
We developed a procedure that expedites the preparation of cyclic peptide-peptoid hybrids using a set of synthetic building blocks, automated Microwave assisted (MW)-assisted solid phase peptide synthesis (SPPS) and on-resin MW-assisted click chemistry protocols

Summary

Introduction

Linear peptides have several disadvantages as drug leads, such as metabolic instability due to enzymatic degradation, hydrolysis or oxidation, short half-life and rapid clearance, poor oral bioavailability and in some cases poor solubility and low membrane permeability (Marqus et al, 2017). Cyclic peptides can be classified into head-to-tail, head-toside chain, side chain-to-tail, and side chain-to-side chain cyclization (Zhang et al, 2019). Several approaches have been used to generate cyclic peptides, such as backbone cyclization (Gilon et al, 1991), peptide stapling (Schafmeister et al, 2000), and native chemical ligation (Dawson et al, 1994). These structures can be formed with chemically stable bonds, such as an amide, lactone, ether, thioether, or disulfide bonds (Qvit et al, 2017). Peptide cyclization can be achieved by using native amino acids side chains, including cysteine disulfide bridges (Góngora-Benítez et al, 2014), amine arylation and alkylation (Lautrette et al, 2016), etc. (Tang et al, 2017; Zhang et al, 2019)

Methods

Results

Conclusion