COVID-19 is a complex disease with short- and long-term ("long-COVID") respiratory, inflammatory and neurological symptoms that are triggered by infection with SARS-CoV-2. Currently used drugs fall into three categories (antiviral antibodies, antiviral drugs and immunosuppressors) generally relying on a single active molecule. Here, the team of Ralf Jockers (Institut Cochin), in close collaboration with the teams of Subhabrata Sen (Shiv Nadar University, School of Natural Sciences, Gautam Buddha Nagar, India) and the team of Morgane Bomsel (Institut Cochin) explored a multi-target strategy by developing an active molecule that displays several molecular targets involved in the pathology of COVID-19. Such an approach has already been successfully applied in other complex pathologies such as cancer and mental disorders.

The authors synthesized a library of compounds based on C2-substituted indolealkylamines (tryptamines and 5-hydroxytryptamines) by targeting three proteins potentially linked to COVID-19, namely the human angiotensin-converting enzyme 2 (hACE2: the main entry receptor of SARS-CoV-2 into the host cell), melatonin receptors (protective effect on clinical symptoms of infection), and calmodulin (involved in the regulation of ACE2 ectodomain detachment). The authors show that two of the synthesized indolealkylamine compounds bind with high affinity to melatonin receptors and modify the functions of calmodulin. These compounds also alter the interaction of the Spike protein of SARS-CoV-2 with ACE2. It is important to note that the compounds tested thus inhibit the entry of SARS-CoV-2 into host cells, and that one of the identified compounds decreases the replication of SARS-CoV-2 with an inhibitory activity on the viral enzyme mPro (the main protease of SARS-CoV-2).

These results, together with the team's recent discovery showing that existing melatonin-derived drugs and their analogues inhibit SARS-CoV-2 infection of the brain, expand the therapeutic potential of indole compounds towards a multi-target approach for the design of new drugs for the prevention and treatment of COVID-19.

This work was funded by the National Research Agency (ANR-RA-COVID-19: ANR-20-COV4-0001). Prof. Sen benefited from a "Visiting professorship" program of Université Paris Cité to exchange with the Jockers team in 2022.