Lysophosphatidic acid type 2 receptor agonists in targeted drug development offer broad therapeutic potential
| Autor: | Andrea Balogh, Shannon W. McCool, Alyssa Boler, Erzsebet Szabo, Leonard R. Johnson, Derek D. Norman, Karin E. Thompson, Sue Chin Lee, Gabor Tigyi |
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| Rok vydání: | 2019 |
| Předmět: |
autotaxin
0301 basic medicine Programmed cell death Rx100 QD415-436 030204 cardiovascular system & hematology Biochemistry 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Endocrinology In vivo Drug Discovery Lysophosphatidic acid Animals Humans Amino Acid Sequence Receptors Lysophosphatidic Acid Receptor gastric erosion radiation mitigator Chemistry secretory diarrhea apoptosis Cell Biology Lipid signaling JLR Perspectives 030104 developmental biology Drug development Apoptosis Cancer research lipids (amino acids peptides and proteins) biological phenomena cell phenomena and immunity Autotaxin DNA Damage Signal Transduction |
| Zdroj: | Journal of Lipid Research, Vol 60, Iss 3, Pp 464-474 (2019) |
| ISSN: | 0022-2275 |
| Popis: | The growth factor-like lipid mediator, lysophosphatidic acid (LPA), is a potent signaling molecule that influences numerous physiologic and pathologic processes. Manipulation of LPA signaling is of growing pharmacotherapeutic interest, especially because LPA resembles compounds with drug-like features. The action of LPA is mediated through activation of multiple types of molecular targets, including six G protein-coupled receptors that are clear targets for drug development. However, the LPA signaling has been linked to pathological responses that include promotion of fibrosis, atherogenesis, tumorigenesis, and metastasis. Thus, a question arises: Can we harness, in an LPA-like drug, the many beneficial activities of this lipid without eliciting its dreadful actions? We developed octadecyl thiophosphate (OTP; subsequently licensed as Rx100), an LPA mimic with higher stability in vivo than LPA. This article highlights progress made toward developing analogs like OTP and exploring prosurvival and regenerative LPA signaling. We determined that LPA prevents cell death triggered by various cellular stresses, including genotoxic stressors, and rescues cells condemned to apoptosis. LPA(2) agonists provide a new treatment option for secretory diarrhea and reduce gastric erosion caused by nonsteroidal anti-inflammatory drugs. The potential uses of LPA(2) agonists like OTP and sulfamoyl benzoic acid-based radioprotectins must be further explored for therapeutic uses. |
| Databáze: | OpenAIRE |
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