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Lipid-membrane-targeting strategies hold great promise to develop broad-spectrum antivirals. However, it remains a big challenge to identify novel membrane-based targets of viruses and virus-infected cells for development of precision targeted approaches. Here, it is discovered that viroporins, viral-encoded ion channels, which have been reported to mediate release of hydrogen ions, trigger membrane acidification of virus-infected cells. Through development of a fine-scale library of gradient pH-sensitive (GPS) polymeric nanoprobes, the cellular membrane pH transitions are measured from pH 6.8-7.1 (uninfection) to pH 6.5-6.8 (virus-infection). In response to the subtle pH alterations, the GPS polymer with sharp response at pH 6.8 (GPS6.8 ) selectively binds to virus-infected cell membranes or the viral envelope, and even completely disrupts the viral envelope. Accordingly, GPS6.8 treatment exerts suppressive effects on a wide variety of viruses including SARS-CoV-2 through triggering viral-envelope lysis rather than affecting immune pathway or viability of host cells. Murine viral-infection models exhibit that supplementation of GPS6.8 decreases viral titers and ameliorates inflammatory damage. Thus, the gradient pH-sensitive nanotechnology offers a promising strategy for accurate detection of biological pH environments and robust interference with viruses. © 2022 Wiley-VCH GmbH.


Yizhe Sun, Lidong Gong, Yue Yin, Lei Zhang, Qiangming Sun, Kai Feng, Yimin Cui, Qiang Zhang, Xuehui Zhang, Xuliang Deng, Fuping You, Dan Lu, Zhiqiang Lin. A Gradient pH-Sensitive Polymer-Based Antiviral Strategy via Viroporin-Induced Membrane Acidification. Advanced materials (Deerfield Beach, Fla.). 2022 May;34(18):e2109580

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PMID: 35229371

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