Recent advances in roles of G-protein coupled receptors in intestinal intraepithelial lymphocytes

The great clinical success of chimeric antigen receptor T cell (CAR-T) and PD-1/PDL-1 inhibitor therapies suggests the drawing of a cancer immunotherapy age. However, a considerable proportion of cancer patients currently receive little benefit from these treatment modalities, indicating that multiple immunosuppressive mechanisms exist in the tumor microenvironment. In this review, we mainly discuss recent advances in small molecular regulators targeting G Protein-Coupled Receptors (GPCRs) that are associated with oncology immunomodulation, including chemokine receptors, purinergic receptors, prostaglandin E receptor EP4 and opioid receptors. Moreover, we outline how they affect tumor immunity and neoplasia by regulating immune cell recruitment and modulating tumor stromal cell biology. We also summarize the data from recent clinical advances in small molecular regulators targeting these GPCRs, in combination with immune checkpoints blockers, such as PD-1/PDL-1 and CTLA4 inhibitors, for cancer treatments.

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Recent Advances in the Drug Discovery and Development of Dualsteric/ Bitopic Activators of G Protein-Coupled Receptors

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666191009164609 ◽

2019 ◽

Vol 19 (26) ◽

pp. 2378-2392 ◽

Cited By ~ 3

Author(s):

Bethany A. Reinecke ◽

Huiqun Wang ◽

Yan Zhang

Keyword(s):

G Protein ◽

Binding Affinity ◽

G Protein Coupled Receptors ◽

Allosteric Modulator ◽

High Binding ◽

Subtype Selectivity ◽

Recent Advances ◽

Allosteric Sites ◽

G Protein Coupled ◽

High Binding Affinity

G protein-coupled receptors (GPCRs) represent the largest family of proteins targeted by drug design and discovery efforts. Of these efforts, the development of GPCR agonists is highly desirable, due to their therapeutic robust utility in treating diseases caused by deficient receptor signaling. One of the challenges in designing potent and selective GPCR agonists lies in the inability to achieve combined high binding affinity and subtype selectivity, due to the high homology between orthosteric sites among GPCR subtypes. To combat this difficulty, researchers have begun to explore the utility of targeting topographically distinct and less conserved binding sites, namely “allosteric” sites. Pursuing these sites offers the benefit of achieving high subtype selectivity, however, it also can result in a decreased binding affinity and potency as compared to orthosteric agonists. Therefore, bitopic ligands comprised of an orthosteric agonist and an allosteric modulator connected by a spacer and allowing binding with both the orthosteric and allosteric sites within one receptor, have been developed. It may combine the high subtype selectivity of an allosteric modulator with the high binding affinity of an orthosteric agonist and provides desired advantages over orthosteric agonists or allosteric modulators alone. Herein, we review the recent advances in the development of bitopic agonists/activators for various GPCR targets and their novel therapeutic potentials.

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