bims-limsir 2023-01-15 papers

Bioorg Med Chem Lett. 2023 Jan 09. pii: S0960-894X(23)00004-5. [Epub ahead of print] 129126

Synthesis of 2'-modified N6-methyladenosine phosphoramidites and their incorporation into siRNA.

Anna M Rydzik, Doris Riether, Dirk Gottschling.

A synthesis of 2'-fluoro and 2'-methoxy N6-methyladenosine phosphoramidites and their successful incorporation into oligonucleotides is reported. 2'-fluoro and 2́-methoxy modifications of sugars in siRNAs are known to aid stability and N6-methylation modifies the potency of therapeutic silencing RNAs (siRNA). We demonstrate that a combination of those modifications incorporated into the antisense strand of siRNA leads to efficient knockdown of a target gene in cells. This work broadens the available pool of chemical modifications of therapeutic siRNAs and provides tools for their efficient synthesis.

Keywords: 6-methyladenosine; RNA therapeutics; epigenetics; m6A; siRNA

DOI: https://doi.org/10.1016/j.bmcl.2023.129126

Chem Soc Rev. 2023 Jan 12.

Chemically engineering cells for precision medicine.

Yixin Wang, Zhaoting Li, Fanyi Mo, Ting-Jing Chen-Mayfield, Aryan Saini, Afton Martin LaMere, Quanyin Hu.

Cell-based therapy holds great potential to address unmet medical needs and revolutionize the healthcare industry, as demonstrated by several therapeutics such as CAR-T cell therapy and stem cell transplantation that have achieved great success clinically. Nevertheless, natural cells are often restricted by their unsatisfactory in vivo trafficking and lack of therapeutic payloads. Chemical engineering offers a cost-effective, easy-to-implement engineering tool that allows for strengthening the inherent favorable features of cells and confers them new functionalities. Moreover, in accordance with the trend of precision medicine, leveraging chemical engineering tools to tailor cells to accommodate patients individual needs has become important for the development of cell-based treatment modalities. This review presents a comprehensive summary of the currently available chemically engineered tools, introduces their application in advanced diagnosis and precision therapy, and discusses the current challenges and future opportunities.

DOI: https://doi.org/10.1039/d2cs00142j

Mol Ther Nucleic Acids. 2023 Mar 14. 31 88-104

Chemically modified small interfering RNA targeting Hedgehog signaling pathway for rheumatoid arthritis therapy.

Lang Lin, Shangling Zhu, Hongyu Huang, Lin-Ping Wu, Jianlin Huang.

Rheumatoid arthritis (RA) is an inflammatory disease that leads to disability; however, existing therapies are still unsatisfactory. Activated fibroblast-like synoviocytes (FLSs) play an essential role in synovitis formation and joint destruction in RA. The Hedgehog signaling pathway is aberrantly activated and contributes to the aggressive phenotype of RA-FLSs. However, it remains uncertain whether inhibiting Smoothened (SMO), a critical component of the Hedgehog signaling pathway, is an effective treatment for RA. Here, we design a series of small interfering RNAs (siRNAs) that specifically target the SMO gene. With precise chemical modifications, siRNAs' efficacy and stability are significantly improved, and the off-target effects are minimized. The optimized chemically modified siRNA (si-S1A3-Chol) decreases RA-FLS proliferation and invasiveness without the transfection reagent. Furthermore, si-S1A3-Chol injected intra-articularly effectively alleviates joint destruction and improves motor function in collagen-induced arthritis mouse models. Consequently, our results demonstrate that chemically modified siRNA targeting the Hedgehog signaling pathway may be a potential therapy for RA.

Keywords: Hedgehog signaling; MT: Oligonucleotides: therapies and applications; Smoothened; chemical modification; rheumatoid arthritis; small interfering RNA

DOI: https://doi.org/10.1016/j.omtn.2022.12.008