Design, synthesis and efficacy of novel G protein-coupled receptor kinase 2 inhibitors.
G protein-coupled receptor kinase 2 (GRK2) is a relevant signaling node of the cellular transduction network, playing major roles in the physiology of various organs/tissues including the heart and blood vessels. Emerging evidence suggests that GRK2 is up regulated in pathological situations such as heart failure, hypertrophy and hypertension, and its inhibition offers a potential therapeutic solution to these diseases. We explored the GRK2 inhibitory activity of a library of cyclic peptides derived from the HJ loop of G protein-coupled receptor kinases 2 (GRK2). The design of these cyclic compounds was based on the conformation of the HJ loop within the X-ray structure of GRK2. One of these compounds, the cyclic peptide 7, inhibited potently and selectively the GRK2 activity, being more active than its linear precursor. In a cellular system, this peptide confirms the beneficial signaling properties of a potent GRK2 inhibitor. Preferred conformations of the most potent analog were investigated by NMR spectroscopy.
Dipartimento di Farmacia, "Federico II" University of Naples, Italy.
Alfonso
A
Carotenuto
Ersilia
E
Cipolletta
Isabel
I
Gomez-Monterrey
Marina
M
Sala
Ermelinda
E
Vernieri
Antonio
A
Limatola
Alessia
A
Bertamino
Simona
S
Musella
Daniela
D
Sorriento
Paolo
P
Grieco
Bruno
B
Trimarco
Ettore
E
Novellino
Guido
G
Iaccarino
Pietro
P
Campiglia
D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D047428:Protein Kinase Inhibitors; C496567:GRK2 protein, human; D054769:G-Protein-Coupled Receptor Kinase 2
2,2,4,6,7–pentamethyldihydro benzofuran-5-sulfonyl; 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluoro-phosphate; 9-fluorenyl-methoxycarbonyl; ATP; Cardiovascular system; Cyclic peptides; DCM; DIPEA; DMF; DPC; EDTA; EGTA; ESI; Ethylene diamine tetraacetic acid; Fmoc; GRK2 inhibitors; HBTU; HOBt; LCQ; N,N-diisopropylethyl-amine; N,N-dimethylformamide; N-hydroxy-benzotriazole; NMR conformational analysis; Pbf; Pr(3)SiH or TIS; RP-HPLC; SAR; TFA; Trt; adenosine triphosphate; cAMP; cyclic adenosine monophosphate; dichloromethane; dodecylphosphocholine; electrospray ionization; ethylene glycol tetraacetic acid; liquid chromatography quadrupole mass spectrometry; reversed-phase high performance liquid chromatography; structure–activity relationship; trifluoroacetic acid; triisopropylsilane; trityl