scholarly journals Bombesin Receptor Family Activation and CNS/Neural Tumors: Review of Evidence Supporting Possible Role for Novel Targeted Therapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Terry W. Moody ◽  
Lingaku Lee ◽  
Irene Ramos-Alvarez ◽  
Tatiana Iordanskaia ◽  
Samuel A. Mantey ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Targeted Therapy ◽  
G Protein ◽  
Solid Tumor ◽  
G Protein Coupled Receptors ◽  
Term Survival ◽  
Bombesin Receptor ◽  
G Protein Coupled ◽  
Receptor Family

G-protein-coupled receptors (GPCRs) are increasingly being considered as possible therapeutic targets in cancers. Activation of GPCR on tumors can have prominent growth effects, and GPCRs are frequently over-/ectopically expressed on tumors and thus can be used for targeted therapy. CNS/neural tumors are receiving increasing attention using this approach. Gliomas are the most frequent primary malignant brain/CNS tumor with glioblastoma having a 10-year survival <1%; neuroblastomas are the most common extracranial solid tumor in children with long-term survival<40%, and medulloblastomas are less common, but one subgroup has a 5-year survival <60%. Thus, there is an increased need for more effective treatments of these tumors. The Bombesin-receptor family (BnRs) is one of the GPCRs that are most frequently over/ectopically expressed by common tumors and is receiving particular attention as a possible therapeutic target in several tumors, particularly in prostate, breast, and lung cancer. We review in this paper evidence suggesting why a similar approach in some CNS/neural tumors (gliomas, neuroblastomas, medulloblastomas) should also be considered.

scholarly journals Adhesion GPCRs in Glioblastoma

2021 ◽  
Author(s):  
Gabriele Stephan ◽  
Niklas Ravn-Boess ◽  
Dimitris G Placantonakis
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
The Past ◽  
Novel Treatment ◽  
The Family ◽  
Health And Disease ◽  
Basic Biology ◽  
G Protein Coupled ◽  
Potential Use ◽  
Receptor Family

Abstract Members of the adhesion family of G protein-coupled receptors (GPCRs) have received attention for their roles in health and disease, including cancer. Over the past decade, several members of the family have been implicated in the pathogenesis of glioblastoma. Here, we discuss the basic biology of adhesion GPCRs and review in detail specific members of the receptor family with known functions in glioblastoma. Finally, we discuss the potential use of adhesion GPCRs as novel treatment targets in neuro-oncology.

scholarly journals Drug Repurposing on G Protein-Coupled Receptors Using a Computational Profiling Approach

2021 ◽  
Vol 8 ◽  
Author(s):  
Alessandra de Felice ◽  
Simone Aureli ◽  
Vittorio Limongelli
Keyword(s):  
G Protein ◽  
Drug Targets ◽  
Chemical Properties ◽  
Drug Repurposing ◽  
G Protein Coupled Receptors ◽  
Alignment Algorithm ◽  
Binding Interaction ◽  
Wide Range ◽  
G Protein Coupled ◽  
Receptor Family

G protein-coupled receptors (GPCRs) are the largest human membrane receptor family regulating a wide range of cell signaling. For this reason, GPCRs are highly desirable drug targets, with approximately 40% of prescribed medicines targeting a member of this receptor family. The structural homology of GPCRs and the broad spectrum of applications of GPCR-acting drugs suggest an investigation of the cross-activity of a drug toward different GPCR receptors with the aim of rationalizing drug side effects, designing more selective and less toxic compounds, and possibly proposing off-label therapeutic applications. Herein, we present an original in silico approach named “Computational Profiling for GPCRs” (CPG), which is able to represent, in a one-dimensional (1D) string, the physico-chemical properties of a ligand–GPCR binding interaction and, through a tailored alignment algorithm, repurpose the ligand for a different GPCR. We show three case studies where docking calculations and pharmacological data confirm the drug repurposing findings obtained through CPG on 5-hydroxytryptamine receptor 2B, beta-2 adrenergic receptor, and M2 muscarinic acetylcholine receptor. The CPG code is released as a user-friendly graphical user interface with numerous options that make CPG a powerful tool to assist the drug design of GPCR ligands.

scholarly journals Exploiting cancer’s phenotypic guise against itself: targeting ectopically expressed peptide G-protein coupled receptors for lung cancer therapy

Oncotarget ◽  
2017 ◽  
Vol 8 (61) ◽  
pp. 104615-104637 ◽  
Author(s):  
Mahjabin Khan ◽  
Tao Huang ◽  
Cheng-Yuan Lin ◽  
Jiang Wu ◽  
Bao-Min Fan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Therapy ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Lung Cancer Therapy ◽  
G Protein Coupled ◽  
Peptide G

scholarly journals Structure-guided optimization of light-activated chimeric G-protein coupled receptors

2021 ◽  
Author(s):  
Alexandra-Madelaine Tichy ◽  
Wang Lok So ◽  
Elliot Gerrard ◽  
Harald Janovjak
Keyword(s):  
G Protein ◽  
Protein Complexes ◽  
G Protein Coupled Receptors ◽  
Design Strategies ◽  
Core Domain ◽  
Chimeric Receptors ◽  
Downstream Signaling ◽  
Rational Engineering ◽  
G Protein Coupled ◽  
Receptor Family

G-protein coupled receptors (GPCRs) are the largest human receptor family and involved in virtually every physiological process. One hallmark of GPCR function is the specific coupling of activated receptors to selected downstream signaling pathways. The ability to tune this coupling would permit the development of receptors with new capabilities. GPCRs and G-proteins have been recently resolved structurally at high resolution, but this information was in only very few cases harnessed for a rational engineering of these protein complexes. Here, we demonstrate the structure-guided optimization of coupling in chimeric light-activated GPCRs (OptoXRs). Our hypothesis was that the incorporation of structural GPCR-Gα contacts will lead to improved receptor activity. We first evaluated structure-based alignments as complements to existing sequence-based methods for generation of chimeric receptors. We then show in a prototypical light-activated β2AR that inclusion of α-helical residues forming structural contacts to Gα resulted in receptors with 7- to 20-fold increased function compared to other design strategies. In turn, elimination of GPCR-Gα contacts diminished function. Finally, the efficient receptor design served as a platform for the optimization of a further light-activated receptor and spectral tuning of the photoreceptor core domain. Our work exemplifies how increased OptoXR potency and new functionalities can be achieved through structure-based design towards targeted inputs into cells and cellular networks.

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