Exploiting the Innate Plasticity of the Programmed Cell Death-1 (PD1) Receptor to Design Pembrolizumab H3 Loop Mimics
Alexis D Richaud1, Mehdi Zaghouani1, Guangkuan Zhao1
1Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, FL 33431, USA.
Abstract:
Checkpoint blockade of the immunoreceptor programmed cell death-1 (PD1) with its ligand-1 (PDL1) by monoclonal antibodies such as pembrolizumab provided compelling clinical results in various cancer types, yet the molecular mechanism by which this drug blocks the PD1/PDL1 interface remains unclear. To address this question, we examined the conformational motion of PD1 associated with the binding of pembrolizumab. Our results revealed that the innate plasticity of both C'D and FG loops is crucial to form a deep binding groove (371 Å3 ) across several distant epitopes of PD1. This analysis ultimately provided a rational-design to create pembrolizumab H3 loop mimics [RDYRFDMGFD] into β-hairpin scaffolds. As a result, a 20-residue long β-hairpin peptide 1 e was identified as a first-in-class potent PD1-inhibitor (EC50 of 0.29 μM; Ki of 41 nM).
Insights
Researchers uncovered how pembrolizumab blocks the programmed cell death-1 (PD1) and programmed cell death-1 ligand (PDL1) interaction. A novel peptide inhibitor targeting PD1 was developed, offering a new therapeutic strategy for cancer treatment.
Area of Science:
- Immunology
- Structural Biology
- Drug Discovery
Background:
- Monoclonal antibodies like pembrolizumab targeting the programmed cell death-1 (PD1) and programmed cell death-1 ligand (PDL1) pathway have shown significant clinical success in cancer therapy.
- However, the precise molecular mechanisms by which these antibodies inhibit the PD1/PDL1 interaction are not fully understood.
Purpose of the Study:
- To elucidate the conformational dynamics of PD1 upon binding with pembrolizumab.
- To leverage these insights for the rational design of novel PD1 inhibitors.
Main Methods:
- Analysis of PD1 conformational motion in complex with pembrolizumab.
- Identification of key structural elements (C'D and FG loops) involved in binding.
- Design and synthesis of peptide-based PD1 inhibitors using β-hairpin scaffolds.
Main Results:
- Pembrolizumab binding induces conformational changes in PD1, creating a deep binding groove.
- The plasticity of PD1's C'D and FG loops is essential for forming this groove across multiple epitopes.
- A novel 20-residue β-hairpin peptide (1 9e) was developed as a potent PD1 inhibitor with nanomolar affinity (Ki = 41 nM).
Conclusions:
- The study reveals the structural basis for pembrolizumab's mechanism of action at the PD1/PDL1 interface.
- This work provides a rational design strategy for developing peptide-based inhibitors targeting PD1.
- The identified β-hairpin peptide represents a first-in-class potent PD1 inhibitor with potential therapeutic applications in cancer immunotherapy.
