ACE-2-interacting Domain of SARS-CoV-2 (AIDS) Peptide Suppresses Inflammation to Reduce Fever and Protect Lungs and Heart in Mice: Implications for COVID-19 Therapy

J Neuroimmune Pharmacol. 2021 Mar;16(1):59-70. doi: 10.1007/s11481-020-09979-8. Epub 2021 Jan 11.


COVID-19 is an infectious respiratory illness caused by the virus strain severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and until now, there is no effective therapy against COVID-19. Since SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) for entering into host cells, to target COVID-19 from therapeutic angle, we engineered a hexapeptide corresponding to the ACE2-interacting domain of SARS-CoV-2 (AIDS) that inhibits the association between receptor-binding domain-containing spike S1 and ACE-2. Accordingly, wild type (wt), but not mutated (m), AIDS peptide inhibited SARS-CoV-2 spike S1-induced activation of NF-κB and expression of IL-6 in human lungs cells. Interestingly, intranasal intoxication of C57/BL6 mice with recombinant SARS-CoV-2 spike S1 led to fever, increase in IL-6 in lungs, infiltration of neutrophils into the lungs, arrhythmias, and impairment in locomotor activities, mimicking some of the important symptoms of COVID-19. However, intranasal treatment with wtAIDS, but not mAIDS, peptide reduced fever, protected lungs, improved heart function, and enhanced locomotor activities in SARS-CoV-2 spike S1-intoxicated mice. Therefore, selective targeting of ACE2-to-SARS-CoV-2 interaction by wtAIDS may be beneficial for COVID-19.

Keywords: ACE-2; Arrhythmias; COVID-19; Fever; Lung inflammation; Spike S1.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Intranasal
  • Angiotensin-Converting Enzyme 2 / therapeutic use*
  • Animals
  • Arrhythmias, Cardiac / etiology
  • Arrhythmias, Cardiac / prevention & control
  • COVID-19 / complications*
  • COVID-19 / pathology
  • COVID-19 Drug Treatment*
  • Female
  • Fever / drug therapy*
  • Fever / etiology*
  • Heart Diseases / etiology*
  • Heart Diseases / pathology
  • Heart Diseases / prevention & control*
  • Inflammation / drug therapy*
  • Inflammation / etiology*
  • Interleukin-6 / metabolism
  • Lung Diseases / etiology*
  • Lung Diseases / pathology
  • Lung Diseases / prevention & control*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Motor Activity / drug effects
  • Neutrophil Infiltration / drug effects
  • Peptide Fragments / therapeutic use*
  • Spike Glycoprotein, Coronavirus / toxicity


  • Interleukin-6
  • Peptide Fragments
  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2