Potential therapeutic options for SARS-CoV-2 patients based on FIP strategies: central nervous system invasion and drug coverage

Original article: Perspectives: potential therapeutic options for SARS-CoV-2 patients based on feline infectious peritonitis strategies: central nervous system invasion and drug coverage; 3.4.2020

Mark Olsen, Sarah E. Cook, Vanthida Huang, Niels Pedersen, Brian G. Murphy

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The number of type 2 severe acute respiratory syndrome (SARS-CoV-2) coronavirus infections continues to rise globally, and hospital physicians are currently preparing therapies for FDA-approved therapies as treatment options for SARS-CoV-2. We have been researching anti-cancer therapies for feline infectious peritonitis (FIP) for several years. [1,2], a coronavirus disease with almost 100% mortality in felines. Feline enteric coronavirus (FECV), which is common in many asymptomatic cats, mutates into virulent and lethal FIP coronavirus [3]. We believe that our experimental research in the treatment of FIP may be relevant and applicable to the latest results of in vitro SARS-CoV-2 tests. [4] in the absence of large-scale laboratory and human clinical studies. The FIP coronavirus protease inhibitor (GC376) has been successful in treating FIP in a subset of felines; however, in cases of neurological impairment, the protease inhibitor was unable to prevent the progression of central nervous system (CNS) disease, resulting in neurological FIP and subsequent euthanasia. [5]. The polymerase inhibitor GS-441524 has already shown significant activity in a feline clinical study against FIP [1], but treatment for neurological impairment has yet to be demonstrated. Remdesivir, a prodrug of GS-441524, has high hopes for the treatment of SARS-CoV-2. [6], but is not currently FDA approved and is only available in intravenous form. There is an urgent need for therapies against SARS-CoV-2, with good oral bioavailability and FDA approved, suitable for organs that express SARS-CoV-2 target angiotensin-converting enzyme 2 (ACE2) and can synergize with remedivr. Although detailed experimental results will be reported elsewhere (unpublished data from BGM Laboratory), we believe that our research could help physicians with treatment options in addition to supportive care.

Type 1 severe acute respiratory syndrome (SARS-CoV-1) and SARS-CoV-2 coronavirus target ACE2 as a receptor [7]which is expressed in humans in the lungs, heart, gastrointestinal tract and CNS [8]. SARS-CoV-1 is known to penetrate the CNS via the olfactory nerve and olfactory bulb [9], like other coronaviruses [10]. Anosmia (loss of smell) often occurs in patients with coronavirus disease 2019 (COVID-19), a disease caused by SARS-CoV-2, suggesting that SARS-CoV-2 uses the same route after infection. Almost all beta-coronaviruses enter the CNS [10] and SARS-CoV-1 and SARS-CoV-2 have the same ACE2 receptor. It is also reasonable to assume that a massive brainstem infection in experimental animals after nasal exposure to SARS-CoV-1 [9] can also occur with SARS-CoV-2, which may contribute to sudden respiratory failure, as seen in some patients [10]. It is unclear whether SARS-CoV-2 CNS penetration may also occur in patients with recent blood-brain barrier (BBB) ​​damage following a stroke or other stroke. As we have shown in cats, the consequences of CNS penetration underline the need for a multi-purpose organ-friendly strategy that suppresses SARS-CoV-2 in both the periphery and the brain.

We found that nelfinavir and amodiaquine show in vitro anti-FIP activity that is comparable to chloroquine and is superior to ribavirin, penciclovir, favipiravir and naphamostat against SARS-CoV-2. [4]. Amodiaquin, like chloroquine and hydroxychloroquine, is a CNS-penetrating 4-aminoquinoline antimalarial drug that inhibits hemozoin production in parasites but has been withdrawn from the US market, although it is still available in other countries. Amodiaquine is known to have some antiviral activity and derivatives have been developed to inhibit Ebola virus infection. [11]. Pharmacogenomics has shown that the presence of the CYP450 2C8 * 2 allele contributes significantly to the toxicity of amodiaquine [12]. Suitable monitoring parameters include complete blood counts with differential and liver function tests, as agranulocytosis and hepatotoxicity are serious side effects, with nausea, vomiting and pruritus being mild side effects. Amodiaquine / artesunate is available for the treatment of malaria; is cost effective and available outside the US. This is the third study of 4-aminoquinoline and its coronavirus activity and complements clinical research from China. [13,14]. In addition, it is well known that 4-aminoquinolines penetrate the BBB and have been investigated for broad-spectrum antiviral activity against various viral infections, including Zika viruses. [15], Dengue [16] and Ebola [17]. It may also be useful for those patients who suffer from SARS-CoV-2 in the brainstem. Antiviral mechanisms of chloroquine action may involve altering the release of endosomal RNA [15], altering autophagically dependent viral replication [15] and inhibition of ACE2 glycosylation [18].

Nelfinavir is an older human immunodeficiency virus (HIV) protease inhibitor capable of inhibiting HIV-1 and, to a lesser extent, HIV-2 protease [19], but it is no longer the first choice of treatment. However, it has a spectrum of activity that includes SARS-CoV-1 [20] also FIP coronavirus [21], is orally bioavailable and can reach a plasma concentration of 7.3 mg / l at a dose of 3000 mg twice daily [ 22]. For the treatment of SARS-CoV-1 [23] Other protease inhibitors, including the combination of lopinavir and ritonavir, have been used to treat SARS-CoV-2 in Singapore. [24] and China [25]. However, there are problems with prescribed dose toxicity [24] as well as efficacy in the monotherapy regimen. [25]. The hypothesis of the use of older antiretroviral agents with higher toxicity but potentially wider antiviral activity spectrum is not new. Experimental study of nelfinavir suppressing FIP coronavirus [21] however, it provides additional data to suggest that nelfinavir could be considered as an alternative to SARS-CoV-2. Suitable nelfinavir monitoring parameters include echocardiogram for QT prolongation and torsades de pointes, as well as diarrhea, fatigue (10–20%), lipodystrophy and hyperglycaemia.

These in vitro activities against FIP coronavirus do not replace clinical data and studies, but may provide guidance for therapeutic off-label strategies. Mutation of FECV to FIP coronavirus may provide a paradigm for considering the relationship between different SARS-CoV-2 strains. Nelfinavir, chloroquine, and hydroxychloroquine are FDA-approved, orally bioavailable, and commercially available, and there is at least data on their effect against SARS-CoV-1 or SARS-CoV-2 in vitro. Nelfinavir may be an alternative to lopinavir / ritonavir. Amodiaquine, hydroxychloroquine and chloroquine show the ability to penetrate the CNS. Amodiaquine may be an alternative to chloroquine in areas where it is available. These agents may offer clinicians an additional therapeutic strategy beyond supportive care as monotherapy or in combination.

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