Repurposing of Doxycycline to Hinder the Viral Replication of SARS-CoV-2: From in silico to in vitro Validation

Rajaiah Alexpandi; Mathieu Gendrot; Gurusamy Abirami; Océane Delandre; Isabelle Fonta; Joel Mosnier; Richard Mariadasse; Jeyaraman Jeyakanthan; Shunmugiah Karutha Pandian; Bruno Pradines; Arumugam Veera Ravi

doi:10.3389/fmicb.2022.757418

Repurposing of Doxycycline to Hinder the Viral Replication of SARS-CoV-2: From in silico to in vitro Validation

Front Microbiol. 2022 May 4:13:757418. doi: 10.3389/fmicb.2022.757418. eCollection 2022.

Authors

Rajaiah Alexpandi¹, Mathieu Gendrot^{2

3

4}, Gurusamy Abirami¹, Océane Delandre^{2

3

4}, Isabelle Fonta^{2

3

4

5}, Joel Mosnier^{2

3

4

5}, Richard Mariadasse⁶, Jeyaraman Jeyakanthan⁶, Shunmugiah Karutha Pandian¹, Bruno Pradines^{2

3

4

5}, Arumugam Veera Ravi¹

Affiliations

¹ Laboratory in Microbiology and Marine Biotechnology, Department of Biotechnology, School of Biological Sciences, Alagappa University, Karaikudi, India.
² Parasitology and Entomology Unit, Department of Microbiology and Infectious Diseases, French Armed Forces Biomedical Research Institute, Marseille, France.
³ IRD, SSA, AP-HM, VITROME, Aix-Marseille University, Marseille, France.
⁴ IHU Méditerranée Infection, Marseille, France.
⁵ National Reference Center for Malaria, Marseille, France.
⁶ Structural Biology and Bio-Computing Laboratory, Department of Bioinformatics, Alagappa University, Karaikudi, India.

Abstract

Since the rapid spread of coronavirus disease (COVID-19) became a global pandemic, healthcare ministries around the world have recommended specific control methods such as quarantining infected peoples, identifying infections, wearing mask, and practicing hand hygiene. Since no effective treatment for COVID-19 has yet been discovered, a variety of drugs approved by Food and Drug Administration (FDA) have been suggested for repurposing strategy. In the current study, we predicted that doxycycline could interact with the nucleotide triphosphate (NTP) entry channel, and is therefore expected to hinder the viral replication of SARS-CoV-2 RNA-dependent RNA-polymerase (RdRp) through docking analysis. Further, the molecular dynamics results revealed that the RdRp-Doxycycline complex was structurally relatively stable during the dynamic period (100 ns), and its complex maintained close contact with their active catalytic domains of SARS-CoV-2 RdRp. The molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculation of binding free energy also showed that the doxycycline has worthy affinities with SARS-CoV-2 RdRp. As expected, doxycycline effectively inhibited the viral replication of IHU strains of SARS-CoV-2 (IHUMI-3 and IHUMI-6), identified from the hospitalized patients in IHU Méditerranée Infection (IHUMI), Marseille, France. Moreover, doxycycline inhibited the viral load in vitro at both on-entry and after viral entry of IHU variants of SARS-CoV-2. The results suggest that doxycycline exhibits strains-dependant antiviral activity against COVID-19. As a result, the current study concludes that doxycycline may be more effective in combination with other drugs for better COVID-19 treatment efficacy.

Keywords: COVID-19; SARS-CoV-2; doxycycline; drug repurposing; in silico; in vitro.