A current perspective on applications of macrocyclic-peptide-based high-affinity ligands

Area of Science:

• Biotechnology
• Molecular Biology
• Drug Discovery

Background:

• Monoclonal antibodies offer high affinity and selectivity but face challenges in tissue penetration and cellular uptake due to their large size (~150 kDa).
• Minimizing protein scaffolds or engineering de novo scaffolds are strategies to overcome limitations of large antibody-based therapeutics.
• Various antibody-derived and non-antibody-derived ligands have been developed to address these challenges.

Purpose of the Study:

• To review and compare different classes of engineered protein scaffolds used as alternatives to traditional antibodies.
• To focus on the structure, production, applications, strengths, and weaknesses of these alternative ligands.
• To highlight macrocyclic peptides generated by the Random non-standard Peptides Integrated Discovery (RaPID) system as a promising small-sized ligand class.

Main Methods:

• Literature review of antibody-derived ligands (antibodies, intrabodies, nanobodies) and non-antibody-derived ligands (monobodies, affibodies, macrocyclic peptides).
• Discussion of the structural characteristics and production methods for each ligand class.
• Analysis of the applications, advantages, and limitations of the reviewed scaffolds.

Main Results:

• Antibody-derived ligands like nanobodies offer reduced size compared to full antibodies.
• Non-antibody-derived ligands, such as monobodies and affibodies, provide alternative small scaffold options.
• Macrocyclic peptides from the RaPID system (~2 kDa) demonstrate potent binding capabilities comparable to larger ligands.

Conclusions:

• Engineered protein scaffolds offer significant advantages over traditional monoclonal antibodies, particularly in terms of size and penetration.
• Macrocyclic peptides produced via the RaPID system represent a highly promising class of small, potent ligands for therapeutic and diagnostic applications.
• Further development and application of these minimized scaffolds are expected to advance drug discovery and delivery.