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Peptides, known for their specificity and therapeutic potential, have gained considerable interest in treating a variety of conditions, including cancer, metabolic diseases, and infections. Solid phase peptide synthesis has dominated peptide production due to its ease of use and automation. However, SPPS is inefficient, requiring excess reagents and huge volumes of solvent. Faced with the challenge of producing large volumes of peptide therapeutics, LPPS has emerged as an alternative manufacturing technology able to dramatically improve scalability and environmental sustainability while also reducing costs.

Conventional SPPS involves extensive use of protecting groups and large volumes of trifluoroacetic acid (TFA) for deprotection and cleavage, contributing to inefficiencies and environmental concerns. The need for sustainable practices in peptide synthesis has led to the development of innovative approaches such as minimal-protection solid-phase peptide synthesis (MP-SPPS) and minimal-rinsing SPPS (MR-SPPS). This study explores MP-SPPS, which employs unprotected side-chain amino acids, specifically Fmoc-Arg-OH, Fmoc-His-OH, and Fmoc-Tyr-OH, to streamline the synthesis process. By reducing the need for protecting groups and TFA, MP-SPPS not only diminishes chemical waste but also enhances productivity, achieving a 5.3-fold increase in efficiency compared to traditional methods. Additionally, the integration of MR-SPPS further minimizes solvent usage, highlighting the potential of these sustainable strategies to improve peptide synthesis while addressing environmental impact.

Nucleic acid therapeutics (NATs) have opened up novel therapeutic opportunities for treating diseases such as cancer, retinopathies and neurodegenerative disorders. However, there have been numerous reports of toxicity and potency-related concerns during the development of NATs. Antibody-oligonucleotide conjugates (AOCs) offer an innovative and highly promising approach to help deliver NATs, where precise targeting of disease-associated cell types and tissues can result in enhanced therapeutic efficacy. The use of advanced conjugation techniques to combine the oligonucleotide and antibody, such as click chemistry, provide safe and effective strategies for AOC synthesis. Importantly, more suitable preclinical models and early pre-clinical testing of AOCs are required to investigate their mechanistic behaviour and translational potential. In this review, we present an overview of the chemistry, biology and therapeutic applications of AOCs.