Selective homodimerization of unprotected peptides using hybrid hydroxydimethylsilane derivatives

Abstract

We developed a simple and straightforward way to dimerize unprotected peptide sequences that relies on a chemoselective condensation of hybrid peptides bearing a hydroxydimethylsilyl group at a chosen position (either C-ter, N-ter or side-chain linked) to generate siloxane bonds upon freeze-drying. Interestingly, the siloxane bond sensitivity to hydrolysis is strongly pH-dependent. Thus, we investigated the stability of siloxane dimers in different experimental conditions. For that purpose, ²⁹Si, ¹³C and ¹H NMR spectra were recorded to accurately quantify the ratio of dimer/monomer. More interestingly, we showed that ¹H resonances of the methylene and methyl groups connected to the Si can be used as sensitive probes to monitor siloxane hydrolysis and to determine the half-lives of the dimers. Importantly, we showed that the dimers were rather stable at pH 7.4 (t_1/2 ≈ 400 h) and we applied the dimerization strategy to bioactive sequences. Once optimized, three dimers of the growth hormone releasing hexapeptide (GHRP-6) were prepared. Interestingly, their pharmacological evaluation revealed that the activity of the dimeric ligands could be switched from agonist to inverse agonist depending on the position of dimerization.