Journal
AIDS RESEARCH AND THERAPY
Volume 18, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s12981-021-00399-z
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Funding
- Koch Institute for Integrative Cancer Research at MIT [P30 CA014051]
- (NIH) [P30 CA014051]
- NIH [R01 CA073808, R01 GM044783, P01 AI132132]
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By engineering amino acid substitutions in RNase 1, it has been transformed into a zymogen that can be activated by HIV-1 protease, showing high toxicity towards infected cells.
Background: Targeting RNA is a promising yet underdeveloped modality for the selective killing of cells infected with HIV-1. The secretory ribonucleases (RNases) found in vertebrates have cytotoxic ribonucleolytic activity that is kept in check by a cytosolic ribonuclease inhibitor protein, RI. Methods: We engineered amino acid substitutions that enable human RNase 1 to evade RI upon its cyclization into a zymogen that is activated by the HIV-1 protease. In effect, the zymogen has an HIV-1 protease cleavage site between the termini of the wild-type enzyme, thereby positioning a cleavable linker over the active site that blocks access to a substrate. Results: The amino acid substitutions in RNase 1 diminish its affinity for RI by 10(6)-fold and confer high toxicity for T-cell leukemia cells. Pretreating these cells with the zymogen leads to a substantial drop in their viability upon HIV-1 infection, indicating specific toxicity toward infected cells. Conclusions: These data demonstrate the utility of ribonuclease zymogens as biologic prodrugs.
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