key: cord-0692135-9to7g5fd
authors: Dwek, Raymond A; Bell, John I; Feldmann, Marc; Zitzmann, Nicole
title: Host-targeting oral antiviral drugs to prevent pandemics
date: 2022-03-25
journal: Lancet
DOI: 10.1016/s0140-6736(22)00454-8
sha: 7e60e6686fae9f704bfc643f77a0ae211bd818ba
doc_id: 692135
cord_uid: 9to7g5fd

nan

Unlike bacteria, viruses must use host cells to replicate. This has enabled us to identify the Achilles heel of many viruses. We want to exploit this knowledge for the therapeutic targeting of current major human pathogens, such as coronaviruses and influenza for which there is a great unmet need. The orally available small molecule broad-spectrum antiviral compounds we have developed over many years target the host 1 and are thus resistant to viral mutations. Hosttargeting drugs can also be employed against newly emerging viruses even before detailed information about the virus becomes available. 2, 3 This will be crucial in preventing the inevitable new epidemics from turning into pandemics.

Most enveloped viruses need to use a sugar-mediated pathway in the infected human host cell to form their correct three-dimensional structures, which involves adding and processing glycans on viral envelope glycoproteins. 2, 3 The glycosylation process involves enzymes in the cell trimming the sugars of the viral glycoproteins for entry into this protein folding quality control pathway. Drugs that partially inhibit these enzymes prevent the virus from making proper use of this folding pathway and lead to inhibition of secretion of infectious virus. [4] [5] [6] [7] [8] Over the past 25 years, we have developed a class of drugs called iminosugars-orally available sugar mimetics that are recognised by and inhibit these sugar processing enzymes that most enveloped viruses rely on. 1 The family of iminosugars derive from the parent compound initially isolated from the leaves of the mulberry tree.

Safety and efficacy data in animals accumulated over the past 20 years show that iminosugar derivatives reduce viral levels and increase survival in animal models of chronic hepatitis B infection, 6 hepatitis C, Japanese encephalitis, influenza, 9 and dengue. 7, 8 When tested in vitro against over 31 clinical HIV isolates, including HIV-1, HIV-2, and multidrug resistant strains, iminosugars are active against a diverse panel of HIV-1 from different genetic subtypes and geographical regions, and against HIV-2 isolates and mutants resistant to antiretrovirals. 10 All HIV isolates tested were rendered non-infectious by iminosugar treatment. Similarly, we have shown that iminosugars work against all hepatitis C genotypes tested and all four main dengue serotypes in vitro. 7 When in-vitro testing against SARS-CoV-2 became possible, we showed that, as predicted, iminosugars are also antiviral against this virus. 11, 12 As the drug target is not under the genetic control of the virus, the virus cannot mutate around it as readily, or at all. The iminosugars will also be antiviral against all variants of this coronavirus, including those for which vaccines are not yet available, and any mutants that might arise naturally or in response to direct acting antiviral drugs, such as protease inhibitors (eg, Paxlovid) and polymerase inhibitors (eg, molnupiravir).

We have data (NCT0269629; NCT02061358) that show that iminosugars could be administered at comparably low concentration three times daily for 7 days-ie, as long as required in an acute infection. This dosing regimen affects mainly ER glucosidase II and leads to antiviral effects. In a 2020 study, we made the discovery that a single higher dose of the iminosugar prevents death in mice infected with lethal doses of influenza or dengue virus even if administered days after infection, and that protection correlates with inhibition of ER glucosidase I. 8 This shifts attention to the latter enzyme as a broadspectrum antiviral target for an oral drug that could be administered after infection in a single-dose manner. This would be particularly useful in pandemic settings, and in poorer countries. Support for using ER glucosidase I as a broad-spectrum antiviral target comes from a study 13 that identified two siblings with a deficiency of ER glucosidase l, which is targeted by the single highdose approach. Despite significant hypogammaglobulinaemia, the children had no history of viral disease and were not able to generate immune responses to live viral vaccines. The investigators concluded that there is a strong potential benefit of using inhibitors of glucosidase l as a means of controlling viral infections, especially those that pose a threat of rapid global spreading. But there is no need for complete inhibition of glucosidase I for therapeutic benefit.

We believe that the gravity of the pandemic urgently demands us to try so-called off the beaten track hosttargeting antivirals rather than only the current direct acting antiviral approaches. The use of host-targeting antivirals is supported by encouraging animal and human toxicity data and could provide a broad-spectrum oral antiviral that is mutation-proof. We believe that the higher singledose regimen (at most, two single doses) should be recommended for global ease of use. We want to initially clinically use the generically available potent iminosugar, MON-DNJ (NCT0269629), used in the above high-dose approach studies, for which some phase 1 data are available. The less potent, but generically approved, orally available iminosugar miglustat, 14 could be used at a single high dose to target coronaviruses and influenza as proof of principle. HIV patients have been given high doses of miglustat in a combination trial. 14 The safety of miglustat at lower concentrations is well documented in its routine use in Gaucher's disease for over 20 years. 15 All currently available data make a clinical trial of this novel concept feasible and hence an imperative for promoting public health. This could be a transformational approach. Broad-spectrum, safe orally available antivirals are desperately needed worldwide, not only to help terminate this pandemic but to prevent the next one. This approach urgently needs support to further evaluate its promise to fill a major unmet need.

RAD and NZ report funding for the research from Oxford Glycobiology Endowment. JIB and MF declare no competing interests.

Oxford Antiviral Drug Discovery Unit. SARS CoV-2 Cellular Tracker: Zitzmann lab

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