Catching Common Cold Virus with a Net: Pyridostatin Forms Filaments in Tris Buffer That Trap Viruses—A Novel Antiviral Strategy?

Abstract

<jats:p>The neutrophil extracellular trap (ET) is a eukaryotic host defense machinery that operates by capturing and concentrating pathogens in a filamentous network manufactured by neutrophils and made of DNA, histones, and many other components. Respiratory virus-induced ETs are involved in tissue damage and impairment of the alveolar–capillary barrier, but they also aid in fending off infection. We found that the small organic compound pyridostatin (PDS) forms somewhat similar fibrillary structures in Tris buffer in a concentration-dependent manner. Common cold viruses promote this process and become entrapped in the network, decreasing their infectivity by about 70% in tissue culture. We propose studying this novel mechanism of virus inhibition for its utility in preventing viral infection.</jats:p>

Targeting G-quadruplexes in the rhinovirus genome by Pyridostatin inhibits uncoating and highlights a critical role for sodium ions.

“…We thus attempted to deliver PDS to the viral RNA genome within the native virion by exploiting this phenomenon. All incubations were done in phosphate-buffered saline (PBS) to prevent PDS aggregation into long brils, as we have recently observed for Tris-but not phosphate-based buffers 71 .…”

“…via forming virus-trapping laments as observed in Tris-based buffers (see above and ref. 71 ) or on the overall rate of native to subviral (A + B) particle conversion. However, quanti cation of the viral RNA contained in the 2G2 precipitates showed that the virus incubated in the presence of PDS and recovered from cells 30 min post-infection (pi) in the form of subviral A-and B-particles contained about 70 % more viral RNA than virus pre-incubated without PDS.…”

“…The 1 H-NMR analysis evidenced that both, G11 and G20, bound the GQ stabiliser pyridostatin (PDS; 91,100 ). In all experiments with this compound, we speci cally avoided Tris-buffer as a solvent since we recently found it to promote aggregation of PDS into variably-sized bres 71 . Using phosphate buffer instead, we noted the formation of PDS dimers, which were the dominant species at concentrations ≥ 200 µM.…”

Targeting G-quadruplexes in the rhinovirus genome by Pyridostatin inhibits uncoating and highlights a critical role for sodium ions.

“…We thus attempted to deliver PDS to the viral RNA genome within the native virion by exploiting this phenomenon. All incubations were done in phosphate-buffered saline (PBS) to prevent PDS aggregation into long fibrils, as we have recently observed for Tris-but not phosphate-based buffers 71 .…”

“…via forming virustrapping filaments as observed in Tris-based buffers (see above and ref. 71 ) or on the overall rate of native to subviral (A + B) particle conversion. However, quantification of the viral RNA contained in the 2G2 precipitates showed that the virus incubated in the presence of PDS and recovered from cells 30 min post-infection (pi) in the form of subviral A-and B-particles contained about 70 % more viral RNA than virus pre-incubated without PDS.…”