| Structural highlights
Function
[PD1L1_HUMAN] Involved in the costimulatory signal, essential for T-cell proliferation and production of IL10 and IFNG, in an IL2-dependent and a PDCD1-independent manner. Interaction with PDCD1 inhibits T-cell proliferation and cytokine production.[1] [2]
Publication Abstract from PubMed
Blockade of the immunoinhibitory PD-1/PD-L1 pathway using monoclonal antibodies has shown impressive results with durable clinical antitumor responses. Anti-PD-1 and anti-PD-L1 antibodies have now been approved for the treatment of a number of tumor types whereas the development of small molecules targeting immune checkpoints lags far behind. Here we characterize two classes of macrocyclic-peptide inhibitors directed at the PD-1/PD-L1 pathway. We show that these macrocyclics act by directly binding to PD-L1 and that they are capable of antagonizing PD-L1 signaling and, similarly to antibodies, can restore the function of T-cells. We also provide the crystal structures of two of these small-molecule inhibitors bound to PD-L1. The structures provide rationales for the checkpoint inhibition by these small molecules and description of their small molecule/PD-L1 interfaces provides a blueprint for design of small-molecule inhibitors of the PD-1/PD-L1 pathway.
Bioactive macrocyclic inhibitors of the PD-1/PD-L1 immune checkpoint.,Magiera-Mularz K, Skalniak L, Zak KM, Musielak B, Rudzinska-Szostak E, Berlicki L, Kocik J, Grudnik P, Sala D, Zizigas-Zarganis T, Shaabani S, Domling A, Dubin G, Holak TA Angew Chem Int Ed Engl. 2017 Sep 7. doi: 10.1002/anie.201707707. PMID:28881104[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999 Dec;5(12):1365-9. PMID:10581077 doi:10.1038/70932
- ↑ Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000 Oct 2;192(7):1027-34. PMID:11015443
- ↑ Magiera-Mularz K, Skalniak L, Zak KM, Musielak B, Rudzinska-Szostak E, Berlicki L, Kocik J, Grudnik P, Sala D, Zizigas-Zarganis T, Shaabani S, Domling A, Dubin G, Holak TA. Bioactive macrocyclic inhibitors of the PD-1/PD-L1 immune checkpoint. Angew Chem Int Ed Engl. 2017 Sep 7. doi: 10.1002/anie.201707707. PMID:28881104 doi:http://dx.doi.org/10.1002/anie.201707707
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