Negative Immune Checkpoint Inhibitors

Abstract

Checkpoint inhibitors are a modern therapeutic approach for treating various types of cancer, metabolic diseases, and chronic infections. The main goal of this therapy is to specifically unlock the immune system, allowing it to recognize and eliminate cancer cells or pathogens, primarily through the activation of T lymphocytes. Monoclonal antibodies used in the treatment of various cancers, such as pembrolizumab (Keytruda), nivolumab (Opdivo), and ipilimumab (Yervoy), carry several limitations, primarily due to their large molecular size. The main challenges include limited tissue penetration, long half-life in the body, and the risk of autoimmune responses. Compared to antibodies, small-molecule and peptide inhibitors offer significant advantages related to their molecular structure. These drugs demonstrate a better ability to penetrate hard-to-reach areas, such as the tumor microenvironments, can be administered orally, and often show lower immunogenicity. A new generation of drugs is PROTACs, which combine the ability to direct proteins to degradation with the action of checkpoint inhibitors, contributing to the elimination of proteins responsible for suppressing the immune response. This publication describes small-molecule inhibitors, peptide inhibitors, and PROTAC molecules targeting negative immune checkpoints-CTLA-4, PD-1, VISTA, TIM-3, BTLA-4, LAG-3, and TIGIT.

Keywords: PROTAC; immune checkpoint; peptide inhibitors; small-molecule inhibitors.

Figure 1

The effect of small-molecule and peptide inhibitors on negative immune checkpoint receptors and their ligands on inactive T cells. The figure shows the schematic interactions between negative ICs on inactive T cells and their ligands expressed on antigen-presenting cells (APCs) or tumor cells. These interactions—PD-1/PD-L1 or PD-L2, CTLA-4/B7.1 or B7.2, PSGL-1/VISTA and VISTA/VSIG-3, BTLA/HVEM, TIM-3/Gal-9, LAG-3/FGL1, and TIGIT/CD155 or CD112—suppress T cell activity and enable immune evasion by tumor cells. The graphic highlights the blockade of these interactions using small-molecule and peptide inhibitors (black cross). The ligands and receptors are depicted as colorful, membrane-bound structures forming inhibitory signaling pairs between cells; their shapes approximately reflect the actual molecular architecture of these proteins. Blocking these pathways leads to T cell reactivation, restoring their ability to recognize and eliminate tumor cells. Created with BioRender.com.

Figure 2

Structures of CTLA-4 peptide inhibitors MC-CT-010.

Figure 3

Structures of CTLA-4 small-molecule inhibitors.

Figure 4

Structures of PD-1 small-molecule inhibitors.

Figure 5

Structures of PD-1 peptide inhibitors.

Figure 6

Structure of PD-1 PROTAC and LYTAC.

Figure 7

Structures and sequence of VISTA small-molecule, peptide, and PROTAC inhibitors.

Figure 8

Sequence of BTLA peptide inhibitor.

Figure 9

Structure of PD-1 small-molecule inhibitor.

Figure 10

Structure and sequence of LAG-3 peptide and small-molecule inhibitors.

Figure 11

Structures of TIGIT small-molecule and peptide inhibitors.