Targeting protein-protein interactions with reversible covalent modalities: Non-cysteine chemistries

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Drug Discovery

Background:

• Protein-protein interactions (PPIs) are crucial for cellular functions and are key therapeutic targets.
• Covalent drug design, particularly reversible modulators, offers advantages for engaging challenging PPI targets.
• Cysteine is a common target for reversible covalent drugs, but limitations necessitate exploring alternative chemistries.

Purpose of the Study:

• To review emerging reversible electrophile-nucleophile chemistries for modulating PPIs.
• To highlight the potential of serine and lysine as alternative nucleophilic targets beyond cysteine.
• To explore case studies demonstrating novel reversible covalent strategies for PPI modulation.

Main Methods:

• Literature review of reversible covalent drug design strategies.
• Analysis of electrophile-nucleophile reactions involving amino acid residues.
• Examination of case studies in PPI modulation using diverse covalent chemistries.

Main Results:

• Reversible covalent modulators provide sustained engagement and selectivity for PPI targets.
• Serine and lysine represent promising alternative nucleophilic targets for covalent drug development.
• Expanding beyond cysteine-based strategies broadens the scope for PPI targeting.

Conclusions:

• Emerging reversible covalent chemistries targeting serine and lysine hold significant potential for modulating challenging PPIs.
• Diversifying covalent drug strategies beyond cysteine can overcome limitations and unlock new therapeutic opportunities.
• This review provides a foundation for developing novel covalent therapeutics against PPIs.