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Home , Cobicistat, Entry inhibitor, Favipiravir, Penciclovir, Remdesivir, Ribavirin

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Coronavirus puts drug repurposing on the fast track Existing antivirals and knowledge gained from the SARS and MERS outbreaks gain traction as the fastest route to fght the current epidemic.

hina’s biotech companies have been gearing up to repurpose existing Cdrugs, approved in the West for other , as treatments for the coronavirus outbreak originating in Wuhan. Last month, Hangzhou-based Ascletis Pharma applied to the Chinese authorities to test two HIV protease inhibitors ( and ASC09) in clinical trials to treat COVID-19, the illness caused by the new coronavirus (Table 1). And Suzhou- based BrightGene Bio-Medical Technology announced in early February that it would begin to manufacture ’ (GS-5734), a broad-spectrum investigational antiviral, as a treatment for coronavirus . Remdesivir, originally developed to treat and then dropped, will also be tested by Gilead in partnership with Chinese health authorities in randomized, controlled trials. “The general genomic layout and the general replication kinetics and the biology of the MERS, SARS and [SARS-CoV-2] Virtual screens can potentially accelerate drug discovery, but the predicted compounds still need to be viruses are very similar, so testing drugs tested experimentally. Credit: da-kuk / iStock / Getty Images Plus which target relatively generic parts of these is a logical step,” says Vincent Munster, chief, Viral Ecology with repurposed drugs known to target parts (e.g., 3-chymotrypsin-like protease, Unit, US National Institute of Health. of the replication machinery of other viruses papain-like protease, RNA-dependent RNA Testing approved for other that are similar to those in SARS-CoV-2 polymerase and its helicase), structural indications also makes sense, as these drugs — for instance, with the analog proteins (e.g., the spike glycoprotein) are already mass produced and available and RNA synthesis inhibitor , and accessory proteins. Kaletra is thought to on a large scale. with reverse transcriptase inhibitors inhibit the 3-chymotrypsin-like protease of From the start of the COVID-19 (/ the SARS and MERS coronaviruses and was outbreak, medical practitioners have fumarate) or with Moscow-based associated with improved clinical outcomes followed ’s guidelines set up in Pharmstandard’s membrane fusion inhibitor in a trial against SARS. Ascletis also reported January and treated hospitalized patients . Umifenovir is also in trials as a that a patient with COVID-19 improved with α- combined with the single agent. rapidly when given this HIV protease repurposed drug Kaletra, an approved SARS-CoV-2 is an enveloped, positive- inhibitor combination. cocktail of the HIV protease inhibitors sense, single-stranded RNA β-coronavirus But Erik De Clercq, of the Rega Institute ritonavir and . The World similar to the severe acute respiratory for Medical Research in Leuven, Belgium, Health Organization has noted that this syndrome (SARS) and Middle East says that in searching for or designing combination could provide some clinical respiratory syndrome (MERS) viruses. effective drugs against COVID-19: “We benefit. Kaletra, manufactured by AbbVie, Potential antiviral targets encoded by should stay away from antivirals known is also being tested in other combinations, the viral genome include non-structural to be acting at targets not playing a role in

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Table 1 | Selected repurposed drugs in clinical development to treat COVID-19 Drug or cocktail Originator company Status and mechanisms Clinical trials (trial posting date) ASC09/ritonavir, lopinavir/ritonavir, Ascletis, AbbVie, ASC09 is an experimental HIV-1 protease At least three trials (e.g., with or without umifenovir Pharmstandard inhibitor; ritonavir and lopinavir/ritonavir are ChiCTR2000029603, 2/6/20) approved protease inhibitors for HIV/AIDS; umifenovir is an approved against ASC09/, ritonavir/ Ascletis, Gilead, AbbVie See above; oseltamivir is a sialidase inhibitor One trial (NCT04261270, 2/7/20) oseltamivir, oseltamivir approved for influenza Azvudine Zhengzhou Granlen Experimental reverse transcriptase inhibitor One trial (ChiCTR2000029853, PharmaTech drug against HIV-1/AIDS 2/15/20) Various combinations of baloxavir Shionogi, Toyama Chemical is a Cap-dependent Two trials (ChiCTR2000029544, marboxil/ and lopinavir/ endonuclease inhibitor and favipiravir is 2/3/20; ChiCTR2000029548, ritonavir a analog RNA-dependent RNA 2/4/20) polymerase inhibitor approved for influenza A and B; see above Various combinations of / Janssen, Gilead Darunavir and are, respectively, Two trials (NCT04252274, 2/5/20; cobicistat alone or with lopinavir/ an HIV-1 protease inhibitor and inhibitor of ChiCTR2000029541, 2/3/20) ritonavir and thymosin α1 (CYP)3A enzyme, approved as a combination against HIV-1/AIDS. Thymosin α1 is an immune response boosting agent Remdesivir Gilead Phosphoramidate of an analog Two trials (NCT04252664, 2/5/20; used for Ebola and virus outbreaks NCT04257656, 2/6/20) (similar structure to approved HIV reverse transcriptase inhibitors) Chloroquine or Shanghai Zhongxi Endosomal acidification fusion inhibitor At least ten trials (e.g., Pharmaceutical, Shanghai ChiCTR2000029826, 2/2/20; Ziyuan Pharmaceutical, NCT04261517, 2/14/20) Wuhan Wuyao Pharmaceutical Methylprednisolone Generic Synthetic corticosteroid that binds to nuclear One trial (NCT04263402, receptors to dampen proinflammatory cytokines 2/10/20) -2b alone or in Biogen, Merck Interferon alfa-2b is a recombinant cytokine Two trials (NCT04254874, 2/5/20; combination with lopinavir/ritonavir with antiviral properties; ribavirin is a guanine ChiCTR2000029308, 1/23/20) and ribavirin derivative; as above Camrelizumab and thymosin Incyte, Shanghai Hengrui Camrelizumab is a humanized monoclonal Two trials (ChiCTR2000029806, Pharmaceutical (mAb) targeting PD-1 2/14/20; NCT04268537, 2/14/20) Chugai Pharmaceutical, Humanized mAb targeting interleukin-6 One trial (ChiCTR2000029765, Zhejiang Hisun 2/13/20) Pharmaceutical, Jiangsu Qyun Bio-Pharmaceutical

Last search run on 15 February using https://clinicaltrials.gov and http://www.chictr.org.cn. Excludes traditional Chinese medicines and blood-derived products, such as serum from recovered patients and stem cells. All trials are being conducted in China.

the replication of coronaviruses.” coronavirus using HIV drugs; these were the RNA polymerase of the Ebola virus Such drugs include , which protease inhibitors that were designed and so prevents replication. The thinking is targeted at the herpesvirus DNA specifically for HIV,” he says. behind repurposing remdesivir is that polymerase, and lopinavir/ritonavir, Nonetheless, several clinical trials of its broad antiviral activity may render it which are targeted at the HIV protease. Kaletra are underway, either alone or effective against SARS-CoV-2. Indeed, Instead, he would favor targeting a with various combinations of , remdesivir is in two clinical trials that virus-specific such as the RNA- guanosine-analog RNA synthesis inhibitors, began early February, with an estimated dependent RNA polymerase, noting that reverse transcriptase inhibitors or influenza completion date of early April. “Remdesivir coronaviruses do not contain or use a drugs, such as baloxavir marboxil, has quite high efficacy across all different reverse transcriptase. George Painter, oseltamivir and umifenovir (Table 1). coronaviruses and therefore it is one of the president of the Emory Institute for Drug These trials are anticipated to read out prime candidates to start being tested,” says Development, Emory University, is also from the end of May onwards. Munster. The World Health Organization’s cautious about the HIV protease inhibitor Painter is more optimistic about R&D Blueprint report released at the end strategy. “It’s probably a long shot to go Gilead’s investigational drug remdesivir, of January considered remdesivir the most for drug repurposing activity against the a analog antiviral, that blocks promising candidate to treat COVID-19,

380 Nature Biotechnology | VOL 38 | April 2020 | 379–391 | www.nature.com/naturebiotechnology news on the basis of its broad-spectrum activity, At least ten clinical trials are testing current outbreak. One of the authors in vitro and in vivo data for coronaviruses chloroquine, approved as an antimalarial of the preprint, Alex Zhavoronkov, and clinical safety from Ebola virus and autoimmune disease drug. In vitro, the CEO at Insilico Medicine, Hong Kong, disease trials. endosomal acidification fusion inhibitor suggests that finding similarities between In vitro studies published in January blocked infection of a clinical isolate of these novel structures and known drugs have shown remdesivir to be active SARS-CoV-2. could be an option for repurposing — against a clinical isolate of SARS-CoV-2. Most of the drugs in clinical trials and here the speed of machine learning Experimental data in mice infected with (Table 1) inhibit key components of the searches could be particularly useful in the related MERS virus also showed the coronavirus infection lifecycle. These epidemic settings. drug was better than a combination of include into the host cell (blocked But even without SARS-CoV-2 structures lopinavir/ritonavir and interferon beta in by umifenovir, chloroquine or interferon), one can do virtual screening. “For a first improving lung function. And the first viral replication (blocked by lopinavir/ approximation, one can work with the patient in the United States with confirmed ritonavir, ASC09 or darunavir/cobicistat, enzyme structures that we have from COVID-19 improved after being treated which inhibit the 3C-like protease (3CLpro)) SARS coronavirus,” says Rolf Hilgenfeld, for one day with remdesivir, although this and viral RNA synthesis (inhibited by Institute of Biochemistry, University of could not be directly attributed to the drug’s remdesivir, favipiravir, emtricitabine/ Lübeck, Germany. “Of course, there are effect. Since then, remdesivir has been tenofovir alafenamide or ribavirin). The some differences, but most of these won’t shown to reduce the severity of disease, genomic sequence of the SARS-CoV-2 affect the binding sites for inhibitors to the virus replication and damage to the lungs in suggests that there is a high level of sequence substrate,” he says. a non-human primate model of MERS. similarity between the SARS-CoV-2, Even though virtual screening “Broad-spectrum agents are ideally SARS and MERS proteins involved in the makes it possible to discover molecules suited for outbreak situations where we replication cycle. relatively quickly, these compounds still don’t entirely know what we are dealing Targeting viral cellular entry via the need to be experimentally tested — for with in terms of pathogens,” says Bryan spike glycoprotein, which mediates the example, against the virus in cell culture Mounce, assistant professor, Department virus–cell interaction, is another — before any further steps can be taken. of Microbiology and Immunology, Loyola option for repurposing. SARS-CoV-2 uses “Unfortunately, with previous outbreaks, University Chicago. “Although we might angiotensin-converting enzyme 2 (ACE2) there is the experience that not all of these not understand all the mechanisms and the cellular protease transmembrane studies are very sound, they have been done underlying their antiviral activity, it is protease 2 (TMPRSS2) to enter target under tight pressure, and so one has to important that they have as few side effects cells. The marketed TMPRSS2 inhibitor be a little bit cautious about the results,” as possible,” he adds. A second broad- camostat mesylate blocked cellular entry says Hilgenfeld. spectrum antiviral in trials (Table 1) is of the SARS-CoV-2 virus, according to Targeting viral replication with Tokyo-based Toyama Chemical’s RNA an unpublished preprint. And the Janus- drugs such as remdesivir should prevent polymerase inhibitor favipiravir, approved associated kinase (JAK) inhibitor Olumiant asymptomatic, mild or moderate COVID-19 for use against influenza A and B. In an (), approved for rheumatoid cases from progressing to severe disease. in vitro study, this compound did not show arthritis, was identified using machine Yet current drugs in trials might not be strong activity against a clinical isolate of learning algorithms on the basis of its enough for those who are sickest. “Typically SARS-CoV-2. inhibition of ACE2-mediated endocytosis. those presenting themselves at hospitals Another JAK inhibitor, Jakafi (ruxolitinib), will already have severe disease, which is “Broad-spectrum agents are is in trials (combined with mesenchymal associated with . Here, targeting ideally suited for outbreak stem cell infusion) for COVID-19. viral replication might take away the virus The release earlier this month of but not the damage that is very likely situations where we don’t the high-resolution crystal structure of due to the immune response of the patient,” entirely know what we are 3CLpro (Protein Data Bank identifier says Munster. 6LU7) and a Science paper describing the The repurposed pipeline is finite, so dealing with in terms of 3.5-Å-resolution structure of the viral it’s almost certain that novel as well as pathogens.” spike S protein in pre-fusion conformation repurposed drugs will be needed in the should also expedite drug discovery efforts. fight against COVID-19. Those that hold Another HIV protease inhibitor, Janssen’s Researchers who determined the 3CLpro the most promise, Painter notes, are those Prezcobix (darunavir and the boosting agent structure reportedly used it to screen for antivirals with a breadth of activity against cobicistat), is also under evaluation. At the repurposed drugs, identifying the protease not only coronaviruses, but other RNA end of January, Janssen shipped Prezcobix inhibitors , , lopinavir viruses, such as highly pathogenic Ebola to China for in vitro testing. In a statement and ritonavir, the proteasome inhibitor and avian flu viruses.. “If there’s any to Nature Biotechnology, the company carfilzomib, two respiratory syncytial virus message to be had from the current said, “We are aware of anecdotal reports drugs, a schizophrenia medication and an outbreak, it’s that it’s almost inevitable of darunavir potentially having antiviral immunosuppressant. Also on the basis of it will happen again.” ❐ activity against COVID-19. The company the 3CLpro structure, machine learning has no in vitro or clinical data to support algorithms (generative deep learning) Charlotte Harrison the use of darunavir as a treatment for generated several novel potential inhibitors. Canterbury, UK COVID-19.” The recipients of the shipments Turning these into drugs would require a have registered a to test very lengthy drug development process, Published online: 27 February 2020 Prezcobix in combinations. which would probably be longer than the https://doi.org/10.1038/d41587-020-00003-1

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