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Inhibition of human DNA alkylation damage repair enzyme ALKBH2 by HIV protease inhibitor ritonavir

Unnikrishnan P Shaji1, Nikhil Tuti1, S K Alim2

  • 1Department of Biotechnology, Indian Institute of Technology Hyderabad (IITH), Kandi, Sanga Reddy, Telangana 502284, India.

DNA Repair
|August 2, 2024
PubMed

Insights

This study repurposed HIV protease inhibitors to target the DNA repair enzyme ALKBH2, finding that ritonavir inhibits ALKBH2 and sensitizes cancer cells to DNA-damaging agents.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • The human DNA repair enzyme AlkB homologue-2 (ALKBH2) removes methyl adducts from DNA.
  • ALKBH2 is overexpressed in various cancers, presenting a potential therapeutic target.
  • No specific inhibitors for ALKBH2 are currently available.

Purpose of the Study:

  • To investigate the potential of repurposing first-generation HIV protease inhibitors as ALKBH2 inhibitors.
  • To evaluate the anti-cancer activity of these repurposed drugs against ALKBH2.

Main Methods:

  • In vitro binding assays using tryptophan fluorescence and differential scanning fluorimetry were performed.
  • The impact of selected HIV protease inhibitors on ALKBH2's DNA repair activity was assessed.
  • Cancer cell sensitization to methylmethane sulfonate (MMS) was evaluated.

Main Results:

  • Ritonavir, an HIV protease inhibitor, demonstrated significant inhibition of ALKBH2.
  • The inhibition mechanism was identified as competitive.
  • Ritonavir sensitized cancer cells to the alkylating agent MMS.

Conclusions:

  • HIV protease inhibitor ritonavir can act as a competitive inhibitor of ALKBH2.
  • This finding suggests potential for using ritonavir as a DNA repair antagonist in cancer therapy.
  • Further research into ritonavir as a DNA repair inhibitor is warranted.
Keywords:
ALKBH2AlkBAlkylation damageAnti-cancer activityDNA repairDrug repurposingHIV protease inhibitorsRitonavir

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