Remdesivir may hinder the function of Recombination Activating Gene-1 (RAG1)

Abstract

Clinical trials produced conflicting results on the benefits of remdesivir in SARS-CoV-2 infection. While short-term treatment is beneficial, long-term treatment shows no improvement in mortality rate and outcomes, and exhibited worsened clinical status than short-term remdesivir treatment for immunocompetent individuals. On other hand immunocompromised patients were benefitted in long-term remdesivir treatment. Remdesivir exhibited both suppressive and curative effects against covid infection in these individuals. We propose that remdesivir may not be suitable for long-term treatment of immunocompetent patients, as it lowers the immunity through interfering with the endonuclease activity of RAG1, which is a critical enzyme responsible for V(D)J-recombination. In silico study shows, remdesivir, interfere with the DNA cleavage activity of RAG-1, thus lowering immunity. Remdesivir exhibits a higher binding affinity towards the heptamer-binding domain (HBD) of RAG1 than the nonamer-binding domain and exhibited affinity similar to elvitegravir, a RAG1 inhibitor. Interestingly, remdesivir active metabolite GS-443902 has shown stronger binding affinity towards RAG1 HBD, than their intended target viral RdRP. Thus, remdesivir, may be undesirable for long-term treatment in immunocompetent individuals, but may be beneficial for immunocompromised RAG-deficient/ downregulated patients as chances of remdesivir-RAG binding is minimum in those patients. To prove our hypothesis, lymphoid development and V(D)J recombination need to be documented in immunocompetent patients receiving long-term remdesivir. Real-world data in larger trials are necessary to evaluate remdesivir’s effect in B/Tcell depleted/compromised population challenged with covid 19. Studies need to be conducted to show Remdesivir inhibit RAG activity in vitro and V(D)J recombination in vivo.