Small Molecule Inhibited Parathyroid Hormone Mediated cAMP Response by N–Terminal Peptide Binding

Abstract

Ligand binding to certain classes of G protein coupled receptors (GPCRs) stimulates the rapid synthesis of cAMP through G protein. Human parathyroid hormone (PTH), a member of class B GPCRs, binds to its receptor via its N–terminal domain, thereby activating the pathway to this secondary messenger inside cells. Presently, GPCRs are the target of many pharmaceuticals however, these drugs target only a small fraction of structurally known GPCRs (about 10%). Coordination complexes are gaining interest due to their wide applications in the medicinal field. In the present studies we explored the potential of a coordination complex of Zn(II) and anthracenyl–terpyridine as a modulator of the parathyroid hormone response. Preferential interactions at the N–terminal domain of the peptide hormone were manifested by suppressed cAMP generation inside the cells. These observations contribute a regulatory component to the current GPCR–cAMP paradigm, where not the receptor itself, but the activating hormone is a target. To our knowledge, this is the first report about a coordination complex modulating GPCR activity at the level of deactivating its agonist. Developing such molecules might help in the control of pathogenic PTH function such as hyperparathyroidism, where control of excess hormonal activity is essentially required.

Targeting the molecular chaperone SlyD to inhibit bacterial growth with a small molecule

“…As a second control, we employed 9-anthracene methanol in the absence of Cu 2+ , which showed only 10–20% of inhibition at maximum concentration. Third, we replaced Cu 2+ with Zn 2+ in the coordination complex 10 35 . This molecule showed growth inhibition (10–20%) similar to 9-anthracene methanol ( Figure S4 ).…”

DimericR25CPTH(1-34) Activates the Parathyroid Hormone-1 Receptorin vitroand Stimulates Bone Formation in Osteoporotic Female Mice

“…Arg25 resides in the 20-34 (C-terminal region) of PTH(1-34), which plays a significant role in the binding of the ligand to the extracellular domain (ECD) of the PTH1R. In concert with the binding of the 20-24 region of PTH to the ECD, the N-terminal portion of PTH engages the transmembrane domain (TMD) of the PTH1R to then induce the conformational changes involved in G protein coupling and cAMP production (33,(49)(50)(51)(52). The precise binding mode used by dimeric R25C PTH to the PTH1R is unknown, but it may be anticipated that it differs to some extent from that used by the monomeric peptide, due, for example, to the changes in bulk molecular size and display of accessible functional groups.…”

A small-molecule acts as a ‘roadblock’ on DNA, hampering its fundamental processes

“…Many of the currently developed coordination complexes exhibited cytotoxicity under in vitro conditions with either an apoptotic mode of action, or more often with an unknown mechanism, without knowing their cellular targets [12]. However, it is of medical interest to find coordination complexes/small molecules which are able to cross the cell wall/membrane barrier and exhibit cell toxicity by targeting the biomolecules responsible for specific housekeeping pathways [5,13].…”

“…Zn-based coordination compounds have been studied for various activities, including toxicity toward infectious organisms [16]. They exhibit more specific functions, such as the inhibition of caspase-3 activity and promotion of ErbB1-ErbB2 heterodimerization by Zinc pyrithione [17], inhibition of cyclin-dependent kinase CDK1 [18]and inhibition of parathyroid hormone activity [13]. Induction of phosphorylation of the Akt downstream effector glycogen synthase kinase 3 and thus proposed to serve as lead structures for developing antidiabetic drugs and useful tools for regulating glucose metabolism to name but a few examples [19].…”

“…In the present study, a water-soluble coordination complex of Zn(II) and anthracenyl terpyridine ( Figure 1 and S1) [6,13] has been employed as a roadblock of DNA preventing polymerase activity. The Zn 2+ complex inhibited DNA taq polymerase activity under the in vitro conditions of PCR.…”