Peptide-based and small synthetic molecule inhibitors on PD-1/PD-L1 pathway: A new choice for immunotherapy?

Area of Science:

• Immunology
• Pharmacology
• Structural Biology

Background:

• The programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pathway is a key target for cancer immunotherapy.
• Current therapies primarily use monoclonal antibodies (mAbs), which face challenges like production and delivery.
• Small molecule inhibitors present a promising alternative due to their favorable pharmacological properties.

Purpose of the Study:

• To review and analyze non-antibody inhibitors targeting the PD-1/PD-L1 pathway.
• To explore structure-activity relationships (SAR) of these inhibitors.
• To summarize available cocrystal structures to guide future drug design.

Main Methods:

• Literature review of published non-antibody inhibitors of PD-1/PD-L1.
• Analysis of structure-activity relationships (SAR) for identified inhibitors.
• Summary of cocrystal structures, including identified hot spots.

Main Results:

• Several classes of non-antibody inhibitors, including small molecules and cyclopeptides, have been developed.
• Cocrystal structures reveal key binding interactions and hot spots for inhibitor design.
• SAR analysis provides insights into optimizing inhibitor potency and specificity.

Conclusions:

• Non-antibody inhibitors are viable alternatives or supplements to mAbs for targeting the PD-1/PD-L1 pathway.
• Structural information is crucial for the rational design of novel small molecule inhibitors.
• Further research into these inhibitors holds potential for improved cancer therapies.