To increase the chemical space around the well-known GalNAc-ligand as ASGPR-binder, a high-throughput screening campaign was performed, testing approximately 550,000 compounds. After evaluation of the potential screening hits, only one compound, which showed high similarity with guanosine nucleosides, was chosen for further profiling. Crystal structure analysis revealed the coordination of the Ca²⁺-ion within the ASGPR-binding site by the cis-diol motif of the ribose unit as well as an additional π-π-interaction of the purine heterocycle to tryptophan-243. Based on these findings, guanosine was attached via the 5′-OH group to a recently described morpholino-based nucleotide using two different linker units. The resulting morpholino-guanosine building blocks were conjugated to the 5′-end of a literature-known transthyretin targeting small interfering RNA (siRNA), leading to trivalent siRNA-guanosine conjugates, which were tested for their TTR knockdown and exhibited similar potencies as the analogous GalNAc-conjugates in vitro and in vivo.