COVID-19: combining antiviral and anti-inflammatory treatments

Both coronavirus disease 2019 (COVID-19) and severe acute respiratory syndrome (SARS) are characterised by an overexuberant inflammatory response and, for SARS, viral load is not correlated with the worsening of symptoms. In our previous Correspondence to The Lancet, we described how BenevolentAI's proprietary artificial intelligence (AI)-derived knowledge graph, queried by a suite of algorithms, enabled identification of a target and a potential therapeutic against SARS coronavirus 2 (SARS-CoV-2; the causative organism in COVID-19). We identified a group of approved drugs that could inhibit clathrin-mediated endocytosis and thereby inhibit viral infection of cells (appendix). The drug targets are members of the numb-associated kinase (NAK) family—including AAK1 and GAK—the inhibition of which has been shown to reduce viral infection in vitro. Baricitinib was identified as a NAK inhibitor, with a particularly high affinity for AAK1, a pivotal regulator of clathrin-mediated endocytosis. We suggested that this drug could be of use in countering SARS-CoV-2 infections, subject to appropriate clinical testing. To take this work further in a short timescale, a necessity when dealing with a new human pathogen, we re-examined the affinity and selectivity of all the approved drugs in our knowledge graph to identify those with both antiviral and anti-inflammatory properties. Such drugs are predicted to be of particular importance in the treatment of severe cases of COVID-19, when the host inflammatory response becomes a major cause of lung damage and subsequent mortality. Comparison of the properties of the three best candidates are shown in the table. Baricitinib, fedratinib, and ruxolitinib are potent and selective JAK inhibitors approved for indications such as rheumatoid arthritis and myelofibrosis. All three are powerful anti-inflammatories that, as JAK–STAT signalling inhibitors, are likely to be effective against the consequences of the elevated levels of cytokines (including interferon-γ) typically observed in people with COVID-19·2 Although the three candidates have similar JAK inhibitor potencies, a high affinity for AAK1 suggests baricitinib is the best of the group, especially given its once-daily oral dosing and acceptable side-effect profile.The most significant side-effect seen over 4214 patient-years in the clinical trial programmes used for European Medicines Agency registration was a small increase in upper respiratory tract infections (similar to that observed with methotrexate), but the incidence of serious infections (eg, herpes zoster) over 52 weeks' dosing was small (3·2 per 100 patient-years), and similar to placebo.7 Use of this agent in patients with COVID-19 over 7–14 days, for example, suggests side-effects would be trivial.</p

Baricitinib as potential treatment for 2019-nCoV acute respiratory disease

Given the scale and rapid spread of the 2019 novel coronavirus (2019-nCoV) acute respiratory disease, there is an immediate need for medicines that can help before a vaccine can be produced. Results of rapid sequencing of 2019-nCoV, coupled with molecular modelling based on the genomes of related virus proteins,1 have suggested a few compounds that are likely to be effective, including the anti-HIV lopinavir plus ritonavir combination...</p

Identification and characterisation of the angiotensin converting enzyme-3 (ACE3) gene: a novel mammalian homologue of ACE-3

<p><b>Copyright information:</b></p><p>Taken from "Identification and characterisation of the angiotensin converting enzyme-3 (ACE3) gene: a novel mammalian homologue of ACE"</p><p>http://www.biomedcentral.com/1471-2164/8/194</p><p>BMC Genomics 2007;8():194-194.</p><p>Published online 27 Jun 2007</p><p>PMCID:PMC1925091.</p><p></p>(yellow). The zinc ion (spacefill) is coordinated by the zinc binding residues (red). The chloride ions (Cl) of testicular ACE and the locations of the N- and C- termini are also shown. A loop missing in testicular ACE is modelled in red

Identification and characterisation of the angiotensin converting enzyme-3 (ACE3) gene: a novel mammalian homologue of ACE-1

<p><b>Copyright information:</b></p><p>Taken from "Identification and characterisation of the angiotensin converting enzyme-3 (ACE3) gene: a novel mammalian homologue of ACE"</p><p>http://www.biomedcentral.com/1471-2164/8/194</p><p>BMC Genomics 2007;8():194-194.</p><p>Published online 27 Jun 2007</p><p>PMCID:PMC1925091.</p><p></p

Identification and characterisation of the angiotensin converting enzyme-3 (ACE3) gene: a novel mammalian homologue of ACE-6

<p><b>Copyright information:</b></p><p>Taken from "Identification and characterisation of the angiotensin converting enzyme-3 (ACE3) gene: a novel mammalian homologue of ACE"</p><p>http://www.biomedcentral.com/1471-2164/8/194</p><p>BMC Genomics 2007;8():194-194.</p><p>Published online 27 Jun 2007</p><p>PMCID:PMC1925091.</p><p></p>mbrane regions (human, rat, mouse and cow ACE3), along with the known N-terminal signal sequence and C-terminal transmembrane region in testicular ACE. The human ACE3 sequence was restored by compensating for base deletion(s)/insertions and suppressing *stop codons. Positions of the forward and reverse RT-PCR primers are indicated by the arrows beneath the sequence. Accession numbers: Mouse XP_110936; Rat XP_573208; Dog XP_548034; Cow XP_600103

Identification and characterisation of the angiotensin converting enzyme-3 (ACE3) gene: a novel mammalian homologue of ACE-5

<p><b>Copyright information:</b></p><p>Taken from "Identification and characterisation of the angiotensin converting enzyme-3 (ACE3) gene: a novel mammalian homologue of ACE"</p><p>http://www.biomedcentral.com/1471-2164/8/194</p><p>BMC Genomics 2007;8():194-194.</p><p>Published online 27 Jun 2007</p><p>PMCID:PMC1925091.</p><p></p>soform 3). ACE3 can be partly reconstructed from the ACE isoform 3 transcript. For clarity, only relevant exons are shown. Exons (black), introns (grey). Exons numbered according to NCBI gene annotation (ACE) and by comparison to other ACE3 sequences (ACE3). Individual ACE3 exons are identical to isoform 3 except for exons 2 and 11 (both have extra base pairs). Exons 28, 31 and 35 are not part of ACE3 (non-ACE like exons). Exons 1, 4 and part of exon 2 are spliced out in the isoform 3 transcript. * indicates stop codons; ** restored ACE3 stop codon (adapted from NCBI GeneID:1636)

Identification and characterisation of the angiotensin converting enzyme-3 (ACE3) gene: a novel mammalian homologue of ACE-0

<p><b>Copyright information:</b></p><p>Taken from "Identification and characterisation of the angiotensin converting enzyme-3 (ACE3) gene: a novel mammalian homologue of ACE"</p><p>http://www.biomedcentral.com/1471-2164/8/194</p><p>BMC Genomics 2007;8():194-194.</p><p>Published online 27 Jun 2007</p><p>PMCID:PMC1925091.</p><p></p>mbrane regions (human, rat, mouse and cow ACE3), along with the known N-terminal signal sequence and C-terminal transmembrane region in testicular ACE. The human ACE3 sequence was restored by compensating for base deletion(s)/insertions and suppressing *stop codons. Positions of the forward and reverse RT-PCR primers are indicated by the arrows beneath the sequence. Accession numbers: Mouse XP_110936; Rat XP_573208; Dog XP_548034; Cow XP_600103

Identification and characterisation of the angiotensin converting enzyme-3 (ACE3) gene: a novel mammalian homologue of ACE-2

<p><b>Copyright information:</b></p><p>Taken from "Identification and characterisation of the angiotensin converting enzyme-3 (ACE3) gene: a novel mammalian homologue of ACE"</p><p>http://www.biomedcentral.com/1471-2164/8/194</p><p>BMC Genomics 2007;8():194-194.</p><p>Published online 27 Jun 2007</p><p>PMCID:PMC1925091.</p><p></p>d by electrophoresis on a 1% agarose gel. (A) mouse ACE3; (B) actin. Lanes are as follows: 1, positive control (whole mouse RNA with primers for actin); 2, negative control (no RNA); 3, brain; 4, embryo; 5, heart; 6, kidney; 7, liver; 8, lung; 9, ovary; 10, spleen; 11, testis; 12, thymus