LitCovid-sentences  

PMC:7094172 / 24075-27564 JSONTXT 16 Projects

Annnotations TAB TSV DIC JSON TextAE

Id Subject Object Predicate Lexical cue
T194 0-134 Sentence denotes The use of small molecules to stabilize PPI interfaces has been shown to be a viable approach for the development of new therapeutics.
T195 135-1126 Sentence denotes Most compounds created by structure-based design to manipulate the PPI depend on detailed knowledge of the native interacting interfaces.35−37 In contrast, most of the compounds with therapeutic potential that stabilize non-native PPI interfaces were discovered by chance alone.38 The anti-influenza compound nucleozin was initially discovered using a chemical genetics approach, and its ability to stabilize non-native nucleoprotein oligomers was elucidated much later.39,40 Swinholide A, a cytotoxic marine macrolide, has been known to disrupt the actin cytoskeleton and act as an anticancer agent, but it took ten years to discover that it stabilized G-actin as a non-native homodimer complex.41−43 However, these examples did underscore the importance of hydrophobicity as a crucial factor stabilizing protein–protein and protein–ligand associations.44 Here, we demonstrated the possibility of using the hydrophobic interactions on non-native interfaces as targets for virtual screening.
T196 1127-1358 Sentence denotes Combined with suitable selection criteria focusing on both shape and hydrophobic complementarities between the ligand and the receptor, small-molecule compounds that stabilize non-native PPIs may be identified in a rational manner.
T197 1359-1562 Sentence denotes Using the above approach, we successfully identified a compound P3 that affected the biochemical activity of our target protein and showed efficacy against our target pathogen MERS-CoV (Figures 2 and 4).
T198 1563-1754 Sentence denotes P3-mediated non-native MERS-CoV N-NTD dimerization induced abnormal N protein aggregation by influencing the oligomeric behavior of N-CTD and eventually halting its function in RNP formation.
T199 1755-1898 Sentence denotes To the best of our knowledge, this structure-based strategy for targeting non-native interfaces has never been proposed for therapeutic design.
T200 1899-2000 Sentence denotes Thus, non-native interaction interfaces in proteins may comprise a new drug development target class.
T201 2001-2137 Sentence denotes For β-coronaviruses such as MERS-CoV, the amino acids comprising the non-native interaction interface on N-NTD are relatively conserved.
T202 2138-2361 Sentence denotes The hydrophobic pocket surrounding W43 and F135 on monomer 1 is shared among other β-coronaviruses.24,28 The interacting surface on monomer 2, which includes G104, T105, G106, and A109, is also highly conserved (Figure S4).
T203 2362-2519 Sentence denotes This conservation may provide certain advantages when developing compounds with broad-spectrum activity against a target pathogen family, including COVID-19.
T204 2520-2674 Sentence denotes When we tested P3 on mouse hepatitis virus (MHV), we observed a reduction in viral titer, indicating that P3 may also inhibit MHV replication (Figure S5).
T205 2675-2753 Sentence denotes On the other hand, targeting non-native interaction interfaces is not trivial.
T206 2754-2925 Sentence denotes As interface formation is induced by an external agent, computations aimed at predicting native PPI structures may not be able to identify potential non-native interfaces.
T207 2926-3039 Sentence denotes Nevertheless, several stratagems may assist in the identification of potential non-native interaction interfaces.
T208 3040-3162 Sentence denotes One strategy is to search for target protein structures with crystal packing contacts known to be biologically irrelevant.
T209 3163-3489 Sentence denotes Another approach is to identify weakly interacting sites through NMR chemical shift perturbation and hydrogen-deuterium exchange MS.45 Once these potential non-native interaction interfaces are identified, standard screening and then functional characterization may be conducted for small compounds that bind to the interface.