Lysophosphatidic acid type 2 receptor agonists in targeted drug development offer broad therapeutic potential.

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. LPA2 agonists provide a new treatment option for secretory diarrhea and reduce gastric erosion caused by nonsteroidal anti-inflammatory drugs. The potential uses of LPA2 agonists like OTP and sulfamoyl benzoic acid-based radioprotectins must be further explored for therapeutic uses.

Prevention and treatment of secretory diarrhea by the lysophosphatidic acid analog Rx100.

IMPACT STATEMENT: A critical barrier in treating diarrheal disease is easy-to-use effective treatments. Rx100 is a first in class, novel small molecule that has shown efficacy after both subcutaneous and oral administration in a mouse cholera-toxin- and Citrobacter rodentium infection-induced diarrhea models. Our findings indicate that Rx100 a metabolically stable analog of the lipid mediator lysophosphatidic acid blocks activation of CFTR-mediated secretion responsible for fluid discharge in secretory diarrhea. Rx100 represents a new treatment modality which does not directly block CFTR but attenuates its activation by bacterial toxins. Our results provide proof-of-principle that Rx100 can be developed for use as an effective oral or injectable easy-to-use drug for secretory diarrhea which could significantly improve care by eliminating the need for severely ill patients to regularly consume large quantities of oral rehydration therapies and offering options for pediatric patients.

Combined mitigation of the gastrointestinal and hematopoietic acute radiation syndromes by an LPA2 receptor-specific nonlipid agonist.

Pharmacological mitigation of injuries caused by high-dose ionizing radiation is an unsolved medical problem. A specific nonlipid agonist of the type 2 G protein coupled receptor for lysophosphatidic acid (LPA2) 2-[4-(1,3-dioxo-1H,3H-benzoisoquinolin-2-yl)butylsulfamoyl]benzoic acid (DBIBB) when administered with a postirradiation delay of up to 72 hr reduced mortality of C57BL/6 mice but not LPA2 knockout mice. DBIBB mitigated the gastrointestinal radiation syndrome, increased intestinal crypt survival and enterocyte proliferation, and reduced apoptosis. DBIBB enhanced DNA repair by augmenting the resolution of γ-H2AX foci, increased clonogenic survival of irradiated IEC-6 cells, attenuated the radiation-induced death of human CD34(+) hematopoietic progenitors and enhanced the survival of the granulocyte/macrophage lineage. DBIBB also increased the survival of mice suffering from the hematopoietic acute radiation syndrome after total-body irradiation. DBIBB represents a drug candidate capable of mitigating acute radiation syndrome caused by high-dose γ-radiation to the hematopoietic and gastrointestinal system.