System biological investigations of hydroxychloroquine and azithromycin targets and their implications in QT interval prolongation

Chem Biol Interact. 2020 Dec 1;332:109299. doi: 10.1016/j.cbi.2020.109299. Epub 2020 Oct 22.


COVID-2019 pandemic is affecting people worldwide in the absence of an effective treatment strategy. Several suggestive therapeutic options through drug repurposing are recommended, but a complete consensus is not reached. A combination of Hydroxychloroquine (HCQ) and Azithromycin (AZM) has been widely tried and discussed but its administration has also led to potential adversities in patients. Studies are suggesting that most prominent adverse event with HCQ and AZM combination is QT interval prolongation. We studied interaction of HCQ with AZM and subsequent effect of this drug combination on QT interval prolongation. We performed system biological investigation of HCQ and AZM targets and screened important targets and pathways possibly involved in QT interval prolongation. The best core hub protein drug targets involved in QT interval prolongation were identified as HSP90AA1 exclusively associated with HCQ, while AKT1 exclusively associated with AZM on the basis of node degree value. It was found that PI3K/Akt, VEGF, ERBB2 pathways must be given consideration for understanding the role of HCQ and AZM in QT interval prolongation. Conclusion: Computational methods have certain limitations based on source database coverage and prediction algorithms and therefore this data needs experimental correlation to draw final conclusion, but current findings screen targets for QT interval prolongation associated with HCQ and AZM. These proteins and pathways may provide ways to reduce this major risk associated with this combination.

Keywords: Adverse reactions; COVID-19; Cardiac arrhythmia; Drug targets; Network pharmacology.

MeSH terms

  • Azithromycin / adverse effects
  • Azithromycin / therapeutic use*
  • COVID-19 / complications
  • COVID-19 / epidemiology
  • COVID-19 Drug Treatment*
  • Drug Combinations
  • HSP90 Heat-Shock Proteins / genetics
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Hydroxychloroquine / adverse effects
  • Hydroxychloroquine / therapeutic use*
  • Long QT Syndrome / etiology*
  • Pandemics
  • Protein Interaction Maps
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • SARS-CoV-2 / drug effects
  • Signal Transduction / drug effects


  • Drug Combinations
  • HSP90 Heat-Shock Proteins
  • HSP90AA1 protein, human
  • Hydroxychloroquine
  • Azithromycin
  • AKT1 protein, human
  • Proto-Oncogene Proteins c-akt