Sumon Pratihar

All Publications

• Second-Generation Acyl Modifications Stabilize RNA, Support Translation, and Suppress Cytokine Responses. ACS chemical biology Zhong, W., Sun, Q., Fang, L., Pratihar, S., Sanders, N. N., Kool, E. T. 2026

  Abstract

  Bio-reversible 2'-OH polyacylation (cloaking) has been described recently as a post-transcriptional modification strategy for stabilizing RNAs while enabling recovery of biological function after delivery into cells. Here, we probe the chemical space and utility of this method by evaluating a series of new acyl adducts for their ability to maintain protein expression levels after being substituted at high levels (ca. 25% of nucleotides) on transcripts. Reagent designs focused on the inclusion of electron-withdrawing groups near the acyl carbonyl to enhance electrophilicity. Multiple new reagents demonstrated efficient messenger RNA acylation and stabilization of the RNA against thermal cleavage for two days at 37 °C. Cellular transfection experiments with these acylated transcripts showed that certain modifications maintained native or near-native levels of translation of a protein-coding RNA, confirming the robustness of the approach across a broad set of chemotypes. We further report that protein-coding RNAs polyacylated with selected reversible acyl groups show transiently reduced proinflammatory cytokine responses relative to unmodified RNA. Together, these findings expand the functional boundaries of bio-reversible 2'-OH acylation and provide guidance for future development of RNA protection and modification strategies.

  View details for DOI 10.1021/acschembio.6c00657

  View details for PubMedID 42854114

• A SMUG1 Inhibitor Modulates the Excision of Pyrimidine DNA Damage. ACS medicinal chemistry letters Thacker, P. S., Gao, Y., McPherson, L., Lee, A., Averill, A. M., Pratihar, S., Doublié, S., Ford, J. M., Kool, E. T. 2026; 17 (6): 1285-1293

  Abstract

  Elevated activity of DNA repair enzymes that surveil pyrimidine damage has been associated with resistance to antitumor therapies. The DNA base excision repair (BER) enzyme SMUG1 recognizes and excises a number of modified and damaged pyrimidines that arise in cellular DNA, including deoxyuridine and 5-hydroxymethyl-dU, as well as the cytotoxic antitumor pyrimidine 5-fluorodeoxyuridine (5-FdU). Here we report the discovery and development of the first SMUG1 inhibitor scaffolds, derived from a small molecule sphingosine kinase inhibitor identified as a hit in assays against the DNA repair enzyme. Partial structural optimization resulted in compound SU0617, which inhibits SMUG1 with IC50 = 1.5 ± 0.1 μM and has ablated kinase inhibitory activity. We expect that the new inhibitor can be useful as a tool in studies of the overlapping substrate preferences of base excision repair enzymes and in the study of the pathways involved in responses to therapeutic nucleoside drugs.

  View details for DOI 10.1021/acsmedchemlett.6c00051

  View details for PubMedID 42305202

  View details for PubMedCentralID PMC13266643

• A SMUG1 Inhibitor Modulates the Excision of Pyrimidine DNA Damage ACS MEDICINAL CHEMISTRY LETTERS Thacker, P. S., Gao, Y., McPherson, L., Lee, A., Averill, A. M., Pratihar, S., Doublie, S., Ford, J. M., Kool, E. T. 2026

  View details for DOI 10.1021/acsmedchemlett.6c00051

  View details for Web of Science ID 001770300500001

• RNA 2'-OH modification with stable reagents enabled by nucleophilic catalysis. RSC advances Kool, E. T., Pratihar, S., Thacker, P. S., Banerjee, D., Kim, M. J., Shioi, R. 2025; 15 (43): 35749-35755

  Abstract

  RNA modification at 2'-OH has typically required highly reactive acylating species that exhibit short half-lives in water, challenging purification, and limiting shelf lives. Here, we investigate the use of more stable species as electrophilic reagents, employing nucleophilic catalysis to promote reactions. The results show that multiple previously unreported electrophiles can react in high stoichiometric yields with RNA under appropriate catalysis. Most notably, aryl esters can transfer acyl groups to RNA in one hour, but are stable for months even in pure water. The results expand the functional chemotypes of RNA-reactive species, and identify reagent classes with improved stability and selectivity.

  View details for DOI 10.1039/d5ra06314k

  View details for PubMedID 41018161

  View details for PubMedCentralID PMC12466920

• Sequence-Specific Installation of Aryl Groups in RNA via DNA-Catalyst Conjugates. Angewandte Chemie (International ed. in English) Pratihar, S., Zhong, W., Feng, S., Chatterjee, S., Kool, E. T. 2025: e202515681

  Abstract

  Installing functional groups at specific sites in existing RNA molecules remains a challenge for modification, labeling, and therapeutic strategies. Here, we describe the use of DNA oligonucleotides carrying a catalytic amine group to effect the aqueous SNAr arylation of 2'-OH groups at sequence-complementary sites in RNAs. Chloro-pyrimidine electrophiles are shown to react with amino-DNA conjugates, resulting in a proposed transient ammonium aryl intermediate that can react with RNA near the DNA binding site, delivering the heterocycle to the RNA in high yields. In a test of utility, we construct an aryl electrophile carrying an azide group, and apply this strategy to fluorescently label messenger RNAs locally at the polyA tail. We also employ the approach to direct in vitro arylation in the coding region of a messenger RNA, knocking down protein expression selectively in the presence of another coding RNA. This sequence-directed catalytic strategy enables multiple applications in RNA labeling and modification.

  View details for DOI 10.1002/anie.202515681

  View details for PubMedID 40988407