Design, Synthesis, and Evaluation of Neomycin‐Imidazole Conjugates for RNA Cleavage

Abstract

Targeting RNA with synthetic small molecules attracted much interest during recent years as a particularly promising therapeutic approach in a large number of pathologies spanning from genetic disorders, cancers as well as bacterial and viral infections. In this work, we took advantage of a known RNA binder, neomycin, to prepare neomycin-imidazole conjugates mimicking the active site of ribonuclease enzymes able to induce a site-specific cleavage of HIV-1 TAR RNA in physiological conditions. These new conjugates were prepared using a straightforward synthetic methodology and were studied for their ability to bind the target, inhibit Tat/TAR interaction and induce selective cleavage using fluorescencebased assays and molecular docking. We found compounds with nanomolar affinity, promising cleavage activity and the ability to inhibit Tat/TAR interaction with submicromolar IC 50 s.

Small molecules modulating RNA splicing: a review of targets and future perspectives

“…Consistently, a study using the aminoglycoside antibiotic neomycin, coupled with an amino acid histidine, demonstrated RNA degradation capability under physiological conditions. 145 Using the PINAD methodology, two RNA degrader classes targeting unique SARS-CoV-2 genome structures were formulated against G-quadruplexes and betacoronaviral pseudoknots. 143 Their efficacy in degrading targets was validated through in vitro , in cellulo , and in vivo SARS-CoV-2 models.…”

Targeting Ribonucleases with Small Molecules and Bifunctional Molecules

“…Recently, a biphenyl RNase L activator identified via screening of a DNA-encoded library was used in building the dovitinib-RIBOTAC 7 that degraded miR-21 and deactivated a miR-21 -mediated cancer circuit in MDA-MB-231 cells . Apart from RNase L recruiters, bifunctional molecules with a chemical degrader of RNA including imidazole or a bleomycin derivative were developed. − …”

Proximity-Induced Nucleic Acid Degrader (PINAD) Approach to Targeted RNA Degradation Using Small Molecules

“…7 The Duca group has recently reported a similar approach, in which they weaponized the aminoglycoside antibiotic neomycin with an amino acid histidine. 8 For our studies, we developed two series of PINADs using imidazole warheads conjugated to flexible PEG chains, targeting two different structural elements of the genome of SARS-CoV-2, and demonstrated that these molecules are active using in vitro, in cellulo, and in vivo infection models of SARS-CoV-2 (Figure 1b,c).…”