Intranasal Administration of ACIS KEPTIDE™ Prevents SARS-CoV2-Induced Acute Toxicity in K18-hACE2 Humanized Mouse Model of COVID-19: A Mechanistic Insight for the Prophylactic Role of KEPTIDE™ in COVID-19

  1. Gunnar Gottschalk
  2. James F Keating
  3. Kris Kesler
  4. Konstance Knox
  5. Avik Roy
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Abstract

Previously, we have demonstrated that ACIS KEPTIDE™, a chemically modified peptide, selectively binds to ACE-2 receptor and prevents the entry of SARS-CoV2 virionsin vitroin primate kidney Cells. However, it is not known if ACIS KEPTIDE™ attenuates the entry of SARS-CoV2 virusin vivoin lung and kidney tissues, protects health, and prevent death once applied through intranasal route. In our current manuscript, we demonstrated that the intranasal administration of SARS-CoV2 (1*106) strongly induced the expression of ACE-2, promoted the entry of virions into the lung and kidney cells, caused acute histopathological toxicities, and mortality (28%). Interestingly, thirty-minutes of pre-treatment with 50 μg/Kg Body weight ACIS normalized the expression of ACE-2 via receptor internalization, strongly mitigated that viral entry, and prevented mortality suggesting its prospect as a prophylactic therapy in the treatment of COVID-19. On the contrary, the peptide backbone of ACIS was unable to normalize the expression of ACE-2, failed to improve the health vital signs and histopathological abnormalities. In summary, our results suggest that ACIS is a potential vaccine-alternative, prophylactic agent that prevents entry of SARS-CoV2in vivo, significantly improves respiratory health and also dramatically prevents acute mortality in K18-hACE2 humanized mice.

Highlights

  • ACIS KEPTIDE stimulates the internalization of ACE-2 receptor (Fig. 2) and buffers the membrane localization of ACE-2 receptors (Fig. 2, 6 & 8). Intranasal inoculation of SARS-CoV2 upregulates the expression of ACE-2 in lung epithelium (Fig.6) and kidney tubular cells (Fig.8). ACIS KEPTIDE normalizes the expression of ACE-2 in the kidney tubular cells of virus-treated K18-hACE2mice (Fig. 8).

  • ACIS KEPTIDE™<underline>completely prevents</underline>the entry of SARS-CoV2 in Bronchiolar epithelium (Fig.6), alveolar parenchyma (Fig. 6), and kidney tubular cells (Fig.8).

  • ACIS KEPTIDE™ improves the pulmonary (Fig. 5) and renal pathological changes (Fig. 7) caused by the SARS-CoV2 virus insult.

  • Intranasal administration of 0.05% Beta-propiolactone (βPL)-inactivated SARS-CoV2 (1 *106) causes significant death (28%) in K18-hACE2 humanized mice after 24 hrs of intranasal inoculation (<underline>Supplemental videos</underline>) suggesting that SARS-CoV2 does<underline>not</underline>require its infective properties and genetic mechanism to be functional to cause mortality.

  • The peptide backbone of ACIS KEPTIDE™ provides much less and insignificant protection in the prevention of pathological changes in Lungs (Fig.5 & 6) and Kidney (Fig.7 & 8). Peptide failed to normalize the upscaled expression of ACE-2 in kidney tubular cells (Fig.8) of SARS-CoV2-treated K18-hACE2 mice.

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