Ribonuclease zymogen induces cytotoxicity upon HIV-1 infection
Ontology highlight
ABSTRACT: 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 106-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. Supplementary Information
The online version contains supplementary material available at 10.1186/s12981-021-00399-z.
SUBMITTER: Windsor I
PROVIDER: S-EPMC8549155 | biostudies-literature |
REPOSITORIES: biostudies-literature
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