Facile Synthesis of Oligonucleotide Phosphoroselenoates

Se-(2-Cyanoethyl)phthalimide was synthesized from di-(2-cyanoethyl) diselenide. This reagent was found to be an efficient selenium transfer reagent in the synthesis of selenophosphates. Thus, nucleotide H-phosphonate diesters that are formed in situ through the H-phosphonate chemistry undergo quantitative reaction with Se-(2-cyanoethyl)phthalamide. The resulting Se-(2-cyanoethyl) oligonucleotide phosphoroselenoate triesters are subsequently deprotected to give oligonucleotide phosphoroselenoate diesters in excellent yields

Molecular dynamics methodology.

More information regarding the method, considerations, and findings during the molecular dynamic simulations. (PDF)</p

Average docking scores and base pairings relating to the folded RNAs in each model.

Standard deviation provided in brackets. Note: all values relate only to the folded RNAs in the last generation.</p

3D structure alignments of aptamers.

(a) Alignment of the top three aptamers designed by DAPTEV. (b) Alignment of the median three aptamers designed by DAPTEV. (c) Alignment of the best aptamer designed by DAPTEV with three existing aptamers targeting the RBD of the SARS-CoV-2 spike protein. (d) Alignment of the median aptamer designed by DAPTEV with three existing aptamers targeting the RBD of the SARS-CoV-2 spike protein.</p

Folded RNAs docked to the SARS-CoV-2 RBD based on Rosetta-returned scores.

Associated docking scores are in brackets next to the classification of each complex.</p

Depiction of the implemented VAE.

Typical drug discovery and development processes are costly, time consuming and often biased by expert opinion. Aptamers are short, single-stranded oligonucleotides (RNA/DNA) that bind to target proteins and other types of biomolecules. Compared with small-molecule drugs, aptamers can bind to their targets with high affinity (binding strength) and specificity (uniquely interacting with the target only). The conventional development process for aptamers utilizes a manual process known as Systematic Evolution of Ligands by Exponential Enrichment (SELEX), which is costly, slow, dependent on library choice and often produces aptamers that are not optimized. To address these challenges, in this research, we create an intelligent approach, named DAPTEV, for generating and evolving aptamer sequences to support aptamer-based drug discovery and development. Using the COVID-19 spike protein as a target, our computational results suggest that DAPTEV is able to produce structurally complex aptamers with strong binding affinities.</div

Pharmacokinetic study of the prokinetic ABCs liquiritigenin, naringenin and hesperitin following the oral administration of Si–Ni–San decoction to functional dyspepsia patients

1. The pharmacokinetics (PKs) analysis of compounds absorbed after the oral administration of Si-Ni-San (SNS) decoction to functional dyspepsia (FD) patients was designed to detect whether the effects were similar to prokinetics administered to healthy rats, without ethical limitation. 2. First, the absorbed compounds, liquiritigenin (L), naringenin (N) and hesperitin (H) in the plasma were identified by UPLC-MS/MS following the oral administration of SNS decoction to subjects with FD. Next, the natural ratio of LNH in the SNS decoction was determined by UPLC. Third, gastric emptying and intestinal transit after the oral administration of LNH, in combination or alone, was compared with those observed after SNS administration in healthy rats. Additionally, the clinical PKs of LNH was studied. 3. The prokinetic efficacy of LNH administered at their natural ratios (7.5:5:1) increased dose-dependently and was better than the observed efficacy when administered alone in rats. Analysis of the clinical PK parameters, calculated using a one-compartment model, showed that the Cmax parameters of LNH in 3, 4 and 4 h were 639.17, 410.00 and 181.67 μg/L, respectively. 4. The clinical herbal PK analysis of the absorbed LNH preclinical prokinetic compounds, in their natural ratio from SNS, highlights the impact of an herbal translational pharmacology study.</p

SARS-CoV-2 spike protein RBD targeting aptamers.

CoV2-RBD-1C (left), CoV2–6C3 (middle), and nCoV-S1-Apt1 (right) docked to the cropped spike protein.</p

Visualizing the spike protein and the cropped version.

Location of the chosen residue (201A, atom C5, dark blue dot) on the renumbered SARS-CoV-2 spike protein RBD. Note: the full spike protein shown (left) is for reference but the protein file in DAPTEV is cropped. PDB: 6VXX.</p

Flowchart depicting the DAPTEV process for aptamer design.

Flowchart depicting the DAPTEV process for aptamer design.</p