Covalent peptides and proteins for therapeutics

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Biotechnology

Background:

• Covalent small molecule drugs offer advantages in potency and selectivity.
• Many disease-related proteins and protein-protein interactions are considered "undruggable" by traditional small molecules due to a lack of binding pockets.
• Peptide and protein therapeutics can target these challenging surfaces but have historically relied on noncovalent interactions.

Purpose of the Study:

• To explore the application of covalent mechanisms to peptide and protein therapeutics.
• To highlight the chemical advancements enabling covalent biologics.
• To showcase examples of successful covalent peptide and protein drugs.

Main Methods:

• Utilizing unnatural amino acid chemistry to incorporate electrophilic warheads into peptides and proteins.
• Developing specific electrophilic warheads for targeted covalent modification.
• Evaluating the crosslinking ability and therapeutic effects of novel covalent biologics.

Main Results:

• Demonstrated successful crosslinking of target proteins by covalent peptide and protein therapeutics.
• Showcased the potential for enhanced potency, selectivity, and in vivo efficacy.
• Presented the first covalent protein drug targeting previously undruggable proteins.

Conclusions:

• Covalent peptide and protein therapeutics represent a significant advancement in drug development.
• These novel therapeutics can overcome limitations of small molecules for targeting challenging proteins.
• The development of covalent biologics offers a promising strategy for treating diseases with undruggable targets.