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At least two studies suggested that lopinavir/r pharmacokinetics in COVID-19 patients may differ from those seen in HIV-infected patients. In both studies, very high concentrations were observed, exceeding those in HIV-infected patients by 2-3 fold (Schoergenhofer 2020, Gregoire 2020). However, concentrations of protein-unbound lopinavir achieved by current HIV dosing is probably still too low for inhibiting SARS-CoV-2 replication. The EC50 for HIV is much lower than for SARS-CoV-2. It remains to be seen whether these levels will be sufficient for (earlier) treatment of mild cases or as post-exposure prophylaxis. Other PIs For another HIV PI, darunavir, there is no evidence from either cell experiments or clinical observations that the drug has any prophylactic effect (De Meyer 2020). It is hoped that the recently published pharmacokinetic characterization of the crystal structure of the main protease SARS-CoV-2 may lead to the design of optimized protease inhibitors. Virtual drug screening to identify new drug leads that target protease which plays a pivotal role in mediating viral replication and transcription, have already identified several compounds. Six compounds inhibited M(pro) with IC50 values ranging from 0.67 to 21.4 muM, among them two approved drugs, disulfiram and carmofur (a pyrimidine analog used as an antineoplastic agent) drugs (Jin 2020). Others are in development but still pre-clinical (Dai 2020).
2. Various antiviral agents Most coronaviruses attach to cellular receptors via their spike (S) protein. Within a few weeks after the discovery of SARS-CoV-2, several groups elucidated the entry of the virus into the target cell (Hoffmann 2020, Zhou 2020). Similar to SARS-CoV, SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as a key receptor, a surface protein that is found in various organs and on lung AT2 alveolar epithelial cells. The affinity for this ACE2 receptor appears to be higher with SARS-CoV-2 than with other coronaviruses. The hypothesis that ACE inhibitors promote severe COVID-19 courses through increased expression of the ACE2 receptor remains unproven (see chapter Clinical Presentation, page 333).
Human recombinant soluble ACE2 (APN01) HrsACE2 is a therapeutic candidate that neutralizes infection by acting as a decoy. It may act by binding the viral spike protein (thereby neutralizing
COVID Reference ENG 006.9
