Virtual Screening and In Vitro Evaluation of PD-1 Dimer Stabilizers for Uncoupling PD-1/PD-L1 Interaction from Natural Products.

Jrhau Lung,Ming-Szu Hung,Ming-Szu Hung,Ming-Szu Hung,Chih-Cheng Chen,Ying Huang Tsai,Ying Huang Tsai,Kuan-Der Lee,Yu-Ching Lin,Yu-Ching Lin,Yu-Ching Lin,Chien-Hui Hung

doi:10.3390/molecules25225293

Abstract

Genetic mutations accumulated overtime could generate many growth and survival advantages for cancer cells, but these mutations also mark cancer cells as targets to be eliminated by the immune system. To evade immune surveillance, cancer cells adopted different intrinsic molecules to suppress immune response. PD-L1 is frequently overexpressed in many cancer cells, and its engagement with PD-1 on T cells diminishes the extent of cytotoxicity from the immune system. To resume immunity for fighting cancer, several therapeutic antibodies disrupting the PD-1/PD-L1 interaction have been introduced in clinical practice. However, their immunogenicity, low tissue penetrance, and high production costs rendered these antibodies beneficial to only a limited number of patients. PD-L1 dimer formation shields the interaction interface for PD-1 binding; hence, screening for small molecule compounds stabilizing the PD-L1 dimer may make immune therapy more effective and widely affordable. In the current study, 111 candidates were selected from over 180,000 natural compound structures through virtual screening, contact fingerprint analysis, and pharmacological property prediction. Twenty-two representative candidates were further evaluated in vitro. Two compounds were found capable of inhibiting the PD-1/PD-L1 interaction and promoting PD-L1 dimer formation. Further structure optimization and clinical development of these lead inhibitors will eventually lead to more effective and affordable immunotherapeutic drugs for cancer patients.

Highlights

Immune response is tightly balanced between activation and suppression
Several small molecular inhibitors the PD-1/PD-L1 interaction that could potentially overcome small molecular inhibitors disrupting the PD-1/PD-L1 interactionincluding that could potentially overcome these limitations of therapeutic antibodies have been identified, several biphenyl-based these limitations of aromatic therapeutic antibodies beenvinyl identified, including biphenyl-based derivatives
A strong small molecular PD-1/PD-L1 inhibitor was not identified, the current results suggested that more structurally diverse small molecules may be able to regulate the PD-1/PD-L1 interaction and should warrant expansion of the screening scope for discovering more PD-1/PD-L1 inhibitors of a small molecular weight

Summary

Introduction

Immune response is tightly balanced between activation and suppression. Deviation from the balance in either direction can cause diseases, such as autoimmune disease and cancer. Genetic mutations accumulated during cancer development could generate many growth and survival advantages for cancer cells, but these mutations mark cancer cells as targets to be eliminated by the immune system. Cancer cells activate many immune suppressive systems to block the normal function of immune cells. It is believed that if the malfunctioned immune system can be awakened in cancer patients, deadly diseases could be cured more safely and naturally. Many attempts have been made to overcome immune suppression by modulating various co-stimulatory or co-inhibitory molecules. Several successful examples, such as anti-PD-1 and anti-PD-L1 antibodies, have passed clinical trials and served patients with various cancers

Methods

Results

Conclusion