Protease Inhibitors (Ritonavir and ASC09) in Clinical Trials to Treat COVID-19, the Illness Caused by the New Coronavirus (Table 1)
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news IN this section The race to IGF-1R proves its γδ T cell therapy deliver COVID-19 worth as a target companies surge diagnostics p385 p389 p382 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 coronavirus epidemic. hina’s biotech companies have been gearing up to repurpose existing Cdrugs, approved in the West for other viruses, 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 (ritonavir 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 Gilead Sciences’ remdesivir (GS-5734), a broad-spectrum investigational antiviral, as a treatment for coronavirus infection. Remdesivir, originally developed to treat Ebola virus 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 coronaviruses is a logical step,” says Vincent Munster, chief, Viral Ecology with repurposed drugs known to target parts proteins (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 therapies 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 guanosine analog proteins (e.g., the capsid spike glycoprotein) are already mass produced and available and RNA synthesis inhibitor ribavirin, 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 (emtricitabine/tenofovir alafenamide the SARS and MERS coronaviruses and was outbreak, medical practitioners have fumarate) or with Moscow-based associated with improved clinical outcomes followed China’s guidelines set up in Pharmstandard’s membrane fusion inhibitor in a trial against SARS. Ascletis also reported January and treated hospitalized patients umifenovir. Umifenovir is also in trials as a that a patient with COVID-19 improved with α-interferon 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 lopinavir. 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 NATURE BiotECHNOLOGY | VOL 38 | APRIL 2020 | 379–391 | www.nature.com/naturebiotechnology 379 news 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 entry inhibitor against influenza ASC09/oseltamivir, 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 Baloxavir marboxil is a Cap-dependent Two trials (ChiCTR2000029544, marboxil/favipiravir and lopinavir/ endonuclease inhibitor and favipiravir is 2/3/20; ChiCTR2000029548, ritonavir a guanine analog RNA-dependent RNA 2/4/20) polymerase inhibitor approved for influenza A and B; see above Various combinations of darunavir/ Janssen, Gilead Darunavir and cobicistat 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 cytochrome P450 (CYP)3A enzyme, approved as a combination against HIV-1/AIDS. Thymosin α1 is an immune response boosting agent Remdesivir Gilead Phosphoramidate prodrug of an adenine analog Two trials (NCT04252664, 2/5/20; used for Ebola and Marburg virus outbreaks NCT04257656, 2/6/20) (similar structure to approved HIV reverse transcriptase inhibitors) Chloroquine or hydroxychloroquine 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) Interferon alfa-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 antibody (mAb) targeting PD-1 2/14/20; NCT04268537, 2/14/20) Tocilizumab 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 penciclovir, 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 interferons, remdesivir is in two clinical trials that virus-specific protein 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 nucleotide 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