Fernando Albericio is a Research Professor at the University of KwaZulu-Natal (South Africa). His major research interests cover all aspects of peptide synthetic methodology and the synthesis of peptides with therapeutic activities. Lastly, he was working on greening the SPPS processes. He has published 1110 articles, filled 63 patents, and graduated 85 Ph.D. students. He was recently awarded the 2024 Rudinger Award (EPS), the 2024 Meienhofer Award (BPS), the 2024 Lifetime Achievement Award (EPSC), and the 2019 Goodman Award (APS).

Beatriz G. de la Torre obtained her Ph.D. from the University of Barcelona (Spain). After a dilated career in Spain, she is presently a research Professor at KRISP, College of Health Sciences, University of KwaZulu-Natal (Durban, South Africa). She has been working extensively on glyco, nucleo-, and lipopeptides. Her scientific interests are focused more on the discovery of new antimicrobial peptides, including those for fighting tuberculosis, peptide-based vaccines, and peptide-based drug-delivery systems. Lastly, she is also deeply involved in developing GREEN Solid-Phase Peptide Synthesis Strategies.

Abstract

In recent years, pharmaceutical research has increasingly utilized the conjugation of two molecules (typically an antibody or peptide and a small molecule) as a key strategy for drug development. This technique is based on the use of a linker to bind the two moieties. Although monomers of oligoethylene glycol (OEG) are most widely used in this context, there is interest in repeated amino acid oligomers. Monodisperse polysarcosine (PSar) emerges as an excellent option. Dodeca oligomer peptides of Sarcosine (Sar) were synthesized using Fmoc-Sar-OH, Fmoc-(Sar)2-OH, and Fmoc-(Sar)4-OH, respectively, as building blocks, applying DIC and OxymaPure as coupling reagents. The dodeca target peptide was obtained in all three cases; however, small impurities accompanying the main product peak precluded its direct use as linker for conjugation chemistry in drug discovery. Previous studies by our group indicated that ETT works well in combination with DIC for the coupling of steric-hindered amino acids. We therefore proceeded to prepare (Sar)12 using DIC/ETT as coupling reagents. We observed that the use of Fmoc-Sar-OH and Fmoc-(Sar)2-OH to grow the peptide chain led to a mixture containing the desired dodeca peptide along with an additional Sar attachment, i.e., one extra Sar residue in the case of Fmoc-Sar-OH and two extra ones for Fmoc-(Sar)2-OH, detectable only by MS. However, Fmoc-(Sar)4-OH yielded the desired peptide without any additional Sar attachments.

Introduction

Linkerology®, (1) a technique with increasing impact in the drug discovery arena, is usually based on the use of a linear molecule that binds two moieties of a drug. Examples of these can be found in Antibody-Drug Conjugates (ADCs) for cancer, where the linker connects the cytotoxic drug to the antibody, (2) or in the most recent drugs approved for diabetes type 2 or obesity, where the linker connects the peptide drug with the fatty acid responsible for its binding to albumin to extend the in vivo half-life of the drug (3).

In terms of linkers, those most widely used are based on poly- or oligomers of ethylene glycol. Polyethylene glycol (PEG) has been widely employed in drug discovery because it enhances the circulation of half-life medication (4).
Due to the excellent properties of PEG, among which are solubility in water, low cellular toxicity and protein resistance. PEGylated products have been used for the treatment of a variety of conditions, including melanoma, hepatitis, hematological cancer, and autoimmune diseases (5), to reduce the limitations of peptide-based drugs (6).
Unfortunately, clinica ...