RESUMEN
A series of conformationally-restricted analogues of hPTH was prepared, based on the parent peptide agonist, cyclo(Lys(18)-Asp(22))[Ala(1),Nle(8),Lys(18),Asp(22),Leu(27)]hPTH(1-31)NH(2) (2, EC(50)=0.29nM). Truncation of 2 at either the N- or C-termini resulted in peptides with reduced agonist activity as measured by stimulation of adenylate cyclase activity in the rat osteosarcoma cell line (ROS 17/2.8). Alanine- and glycine-scanning at the N-terminus of 2 was consistent with data previously obtained on linear hPTH(1-34). Other locations within the primary sequence of hPTH(1-31)NH(2) were evaluated by the placement of the [i, i+4] lactam constraining element. Ring size and lactam orientations at the 18-22 positions were also examined.
Asunto(s)
Hormona Paratiroidea/química , Fragmentos de Péptidos/química , Adenilil Ciclasas/efectos de los fármacos , Secuencia de Aminoácidos , Animales , Humanos , Lactamas/química , Datos de Secuencia Molecular , Hormona Paratiroidea/genética , Hormona Paratiroidea/farmacología , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/farmacología , Unión Proteica , Conformación Proteica , Ingeniería de Proteínas , Ratas , Receptores de Hormona Paratiroidea/agonistas , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
One common synthetic route creates small-molecule libraries directed toward two functionally distinct target families. The novel structural template 1 can independently display the necessary pharmacophore patterns for inhibition of members of two different biomolecular target families, the matrix metalloproteinases (MMPs) or the phosphodiesterases (PDEs). The incorporation of multiple target family directed design elements into combinatorial library design could help expedite the pharmaceutical lead discovery process. Z=OR' (PDE4), H (MMPs).