Challenges and Perspectives in Chemical Synthesis of Highly Hydrophobic Peptides

Abstract

Solid phase peptide synthesis (SPPS) provides the possibility to chemically synthesize peptides and proteins. Applying the method on hydrophilic structures is usually without major drawbacks but faces extreme complications when it comes to "difficult sequences." These includes the vitally important, ubiquitously present and structurally demanding membrane proteins and their functional parts, such as ion channels, G-protein receptors, and other pore-forming structures. Standard synthetic and ligation protocols are not enough for a successful synthesis of these challenging sequences. In this review we highlight, summarize and evaluate the possibilities for synthetic production of "difficult sequences" by SPPS, native chemical ligation (NCL) and follow-up protocols.

The multifaceted nature of antimicrobial peptides: current synthetic chemistry approaches and future directions

“…[246][247][248] For these reasons, the chemical synthesis of AMPs is often the more practical approach, particularly since the advent of solid-phase techniques, which have made the process rapid, efficient, and reliable. [249][250][251][252] Solid-phase peptide synthesis (SPPS), initially introduced by Merrifield, is the most commonly used method to produce peptides of small to medium size (up to 50 residues). [253][254][255] SPPS involves attaching the C-terminal aa of the AMP to a polymeric solid support, usually via a cleavable chemical linker, followed by successive deprotections and couplings of the aa building blocks to enable peptide chain elongation.…”

Antiplasmodial Potential of Indonesian Medicinal Plants

“…Also, antimalarial drug resistance is a major hurdle. Peptides [23,24] and amino acidmalaria drug conjugated [25][26][27] were reported for their antiplasmodial activity, however the chemical synthesis of hydrophobic peptide was very challenging [28,29]. Tropical plants are well known as source of bioactive compounds, thus they are potential for the development of a new class antimalarial agent.…”

Looking back: Developments in chemical protein synthesis in 2020

“…Secondary structure formation during SPPS is one of the major drawbacks for growing peptide chains. Various methods including pseudoproline‐dipeptides, post‐synthesis cleavable auxiliaries, and solubilizing self‐immolating linkers have been applied successfully to overcome the above limitation 3 . However, all methods have their own drawbacks such as high costs, being time consuming, and difficult synthesis rendering them for use by specialized laboratories only.…”