Peptide Blocking CTLA-4 and B7-1 Interaction.

Stepan V. Podlesnykh,Andrei I. Chapoval,Anastasia Gordeeva,Andrei I. Khlebnikov,Kristina E. Abramova

doi:10.3390/molecules26020253

Abstract

Discovery of the B7 family immune checkpoints such as CTLA-4 (CD152), PD-1 (CD279), as well as their ligands B7-1 (CD80), B7-2 (CD86), B7-H1 (PD-L1, CD274), and B7-DC (PD-L2, CD273), has opened new possibilities for cancer immunotherapy using monoclonal antibodies (mAb). The blockade of inhibitory receptors (CTLA-4 and PD-1) with specific mAb results in the activation of cancer patients’ T lymphocytes and tumor rejection. However, the use of mAb in clinics has several limitations including side effects and cost of treatment. The development of new low-molecular compounds that block immune checkpoints’ functional activity can help to overcome some of these limitations. In this paper, we describe a synthetic peptide (p344) containing 14 amino acids that specifically interact with CTLA-4 protein. A 3D computer model suggests that this peptide binds to the 99MYPPPY104 loop of CTLA-4 protein and potentially blocks the contact of CTLA-4 receptor with B7-1 ligand. Experimental data confirm the peptide-specific interaction with CTLA-4 and its ability to partially block CTLA-4/B7-1 binding. The identified synthetic peptide can be used for the development of novel immune checkpoint inhibitors that can block CTLA-4 functional activity for cancer immunotherapy.

Highlights

Receptors for the B7 family ligands expressed on the surface of T lymphocytes can deliver both stimulating and inhibitory signals that regulate the immune response [1,2].Inhibitory receptor CTLA-4 (CD152) interact with ligands B7-1 (CD80) and B7-2 (CD86), while PD-1 (CD279) receptor binds B7-H1 (PD-L1, CD274) and B7-DC (PD-L2, CD273).These molecules are termed as immunological checkpoints [1,2]
It appears that the identified peptide interacts with the 99MYPPPY104 amino acid sequence loop of the CTLA-4 molecule which is responsible for the binding of CTLA-4 with
330034 peptides presented microarrays, interacted with repeptides out of peptides presented on microarrays, interacted with combinant CTLA-4Fc protein

Summary

Introduction

Receptors for the B7 family ligands expressed on the surface of T lymphocytes can deliver both stimulating and inhibitory signals that regulate the immune response [1,2]. Inhibitory receptor CTLA-4 (CD152) interact with ligands B7-1 (CD80) and B7-2 (CD86), while PD-1 (CD279) receptor binds B7-H1 (PD-L1, CD274) and B7-DC (PD-L2, CD273) These molecules are termed as immunological checkpoints [1,2]. Low molecular weight agents that block immunological checkpoints can overcome some problems associated with the use of mAb for cancer therapy [7,8]. We introduce a peptide (p344), which can bind the CTLA-4 molecule This peptide was identified using microarrays containing 330034 peptides with random amino acid sequences [15,16,17]. It appears that the identified peptide interacts with the 99MYPPPY104 amino acid sequence loop of the CTLA-4 molecule which is responsible for the binding of CTLA-4 with. Used for immunotherapy of cancer and other cer and other immunologically immunologically dependent diseases

Results and Discussion

99 MYPPPY104

Model of CTLA-4

Interaction

Methods

Materials and Methods