COMPOSITIONS AND METHODS FOR TREATING VIRAL INFECTIONS

Abstract

Described herein are compounds, compositions, kits, methods, and the uses thereof for treating diseases caused at least in part by virus infection.

Claims

1.-15. (canceled)

16. A method for treating a viral infection in a host animal, the method comprising administering to the host animal a composition comprising a therapeutically effective amount of one or more cholesterol-lowering agents, one or more cholesterol absorption inhibitors, or a combination thereof.

17. (canceled)

18. A method for treating a viral infection in a host animal, the method comprising administering to the host animal a composition comprising a therapeutically effective amount of one or more compounds capable of targeting vWF, inhibiting vWF-platelet interaction, or both.

19. (canceled)

20. The method of any claim 16 further comprising administering to the host animal one or more angiotensin receptor blockers, one or more protease inhibitors, or a combination thereof.

21. The method of claim 16 further comprising administering to the host animal one or more vitamins, one or more antioxidants, or a combination thereof.

22. The method of claim 16 wherein the virus is an enveloped virus.

23. The method of claim 16 wherein the virus is a RNA virus.

24. The method of claim 16 wherein the virus is positive-sense virus.

25. The method of claim 16 wherein the virus is a single stranded virus.

26. The method of claim 16 wherein the virus is a Coronaviridae.

27. The method of claim 16 wherein the virus is a Orthocoronavirinae.

28. The method of claim 16 wherein the virus uses, at least in part, host cell ACE2 receptors for entry.

29. The method of claim 16 wherein the virus uses, at least in part, an host cell serine protease for entry, for infection, or for both.

30. The method of claim 1 wherein the cholesterol-lowering agent is atorvastatin, simvastatin, or rosuvastatin, or a salt of the foregoing.

31. The method of claim 1 wherein the cholesterol absorption inhibitor is ezetimibe.

32. The method of claim 1 wherein the combination of cholesterol-lowering agents and cholesterol absorption inhibitor is a mixture of atorvastatin and ezetimibe.

33. The method of claim 2 further comprising administering to the host animal one or more angiotensin receptor blockers, one or more protease inhibitors, or a combination thereof.

34. The method of claim 2 further comprising administering to the host animal one or more vitamins, one or more antioxidants, or a combination thereof.

35. The method of claim 2 wherein the compound is caplacizumab.

36. The method of claim 2 wherein the composition further comprises one or more angiotensin receptor blockers, one or more protease inhibitors, or a combination thereof.

37. The method of claim 2 wherein the composition further comprises one or more vitamins, one or more antioxidants, or a combination of the foregoing.

Description

DETAILED DESCRIPTION

[0025] Several illustrative embodiments of the invention are described by the following clauses:

[0026] A composition for treating a viral infection, the composition comprising one or more cholesterol-lowering agents, cholesterol absorption inhibitors, or a combination thereof.

[0027] A composition for treating a viral infection, the composition consisting essentially of one or more cholesterol-lowering agents, cholesterol absorption inhibitors, or a combination thereof.

[0028] The composition of any one of the preceding clauses wherein the cholesterol-lowering agent is atorvastatin, simvastatin, or rosuvastatin, or a salt of the foregoing.

[0029] The composition of the preceding clauses wherein the cholesterol-lowering agent is atorvastatin.

[0030] The composition of the preceding clause wherein the cholesterol absorption inhibitors is ezetimibe.

[0031] The composition of any one of the preceding clauses wherein the combination of cholesterol-lowering agents and cholesterol absorption inhibitor is atorvastatin/ezetimibe.

[0032] A composition for treating a viral infection, the composition comprising one or more compounds capable of targeting vWF and inhibiting vWF-platelet interaction.

[0033] A composition for treating a viral infection, the composition consisting essentially of one or more compounds capable of targeting vWF and inhibiting vWF-platelet interaction.

[0034] The composition of any one of the preceding clauses wherein the compound capable of targeting vWF and inhibiting vWF-platelet interaction is caplacizumab.

[0035] The composition of any one of the preceding clauses wherein the composition further comprises one or more angiotensin receptor blockers, including angiotensin II receptor blockers.

[0036] The composition of any one of the preceding clauses wherein the composition further comprises one or more protease inhibitors.

[0037] The composition of any one of the preceding clauses wherein the composition further comprises one or more protease inhibitors selected from the group consisting of aprotinin, laskowski inhibitors, lympho-epithelial kazal-type-related inhibitor (lekti), leupeptin, camostat, β-conglycinin, aptivus (tipranavir), reyataz (atazanavir), crixivan, idv (indinavir), prezista (darunavir), lexiva (fosamprenavir), invirase (saquinavir), kaletra (lopinavir/ritonavir), viracept (nelfinavir), norvir (ritonavir), and salts thereof.

[0038] The composition of any one of the preceding clauses wherein the composition further comprises one or more protease inhibitors selected from the group consisting of irbesartan, azilsartan (Edarbi), candesartan (Atacand), eprosartan (Teveten), irbesartan (Avapro), telmisartan (Micardis), valsartan (Diovan, Prexxartan), losartan (Cozaar), olmesartan (Benicar), entresto (sacubitril/valsartan), byvalson (nebivolol/valsartan), and salts thereof.

[0039] The composition of any one of the preceding clauses wherein the protease inhibitor is aprotinin, or a salt thereof.

[0040] The composition of any one of the preceding clauses wherein the protease inhibitor is irbesartan, or a salt thereof.

[0041] The composition of any one of the preceding clauses wherein the composition further comprises one or more vitamins, one or more antioxidants, or a combination of the foregoing.

[0042] The composition of any one of the preceding clauses wherein the composition further one or more antioxidants.

[0043] The composition of any one of the preceding clauses wherein the composition further comprises lycopene.

[0044] A kit for treating a viral infection, the kit comprising a composition of any one of the preceding clauses; and instructions for administering the pharmaceutically active ingredients therein.

[0045] A kit for treating a viral infection, the kit consisting essentially of a composition of any one of the preceding clauses; and instructions for administering the pharmaceutically active ingredients therein.

[0046] Use of one or more cholesterol-lowering agents, cholesterol absorption inhibitors, or a combination thereof in the manufacture of a medicament for treating a viral infection.

[0047] Use of one or more compounds capable of targeting vWF and/or inhibiting vWF-platelet interaction in the manufacture of a medicament for treating a viral infection.

[0048] A method for treating a viral infection in a host animal, the method comprising administering to the host animal a therapeutically effective amount of one or more cholesterol-lowering agents, cholesterol absorption inhibitors, or a combination thereof.

[0049] A method for treating a viral infection in a host animal, the method comprising administering to the host animal a composition consisting essentially of a therapeutically effective amount of one or more cholesterol-lowering agents, cholesterol absorption inhibitors, or a combination thereof.

[0050] A method for treating a viral infection in a host animal, the method comprising administering to the host animal a therapeutically effective amount of one or more compounds capable of targeting vWF and/or inhibiting vWF-platelet interaction.

[0051] A method for treating a viral infection in a host animal, the method comprising administering to the host animal a composition consisting essentially of a therapeutically effective amount of one or more compounds capable of targeting vWF and/or inhibiting vWF-platelet interaction.

[0052] The method of the preceding clauses further comprising administering to the host animal one or more angiotensin receptor blockers, including angiotensin II receptor blockers, one or more protease inhibitors, or a combination thereof.

[0053] The method of any one of the preceding clauses wherein the composition further comprises one or more protease inhibitors selected from the group consisting of aprotinin, laskowski inhibitors, lympho-epithelial kazal-type-related inhibitor (lekti), leupeptin, camostat, β-conglycinin, aptivus (tipranavir), reyataz (atazanavir), crixivan, idv (indinavir), prezista (darunavir), lexiva (fosamprenavir), invirase (saquinavir), kaletra (lopinavir/ritonavir), viracept (nelfinavir), norvir (ritonavir), and salts thereof.

[0054] The method of any one of the preceding clauses wherein the composition further comprises one or more protease inhibitors selected from the group consisting of irbesartan, azilsartan (Edarbi), candesartan (Atacand), eprosartan (Teveten), irbesartan (Avapro), telmisartan (Micardis), valsartan (Diovan, Prexxartan), losartan (Cozaar), olmesartan (Benicar), entresto (sacubitril/valsartan), byvalson (nebivolol/valsartan), and salts thereof.

[0055] The method of any one of the preceding clauses wherein the protease inhibitor is aprotinin, or a salt thereof.

[0056] The method of any one of the preceding clauses wherein the protease inhibitor is irbesartan, or a salt thereof.

[0057] The method of the preceding clauses further comprising administering to the host animal one or more vitamins, one or more antioxidants, or a combination thereof.

[0058] The composition, kit, use, or method of any one of the preceding clauses wherein the vitamin is a vitamin D or an analog or derivative thereof.

[0059] The composition, kit, use, or method of any one of the preceding clauses wherein the antioxidant is lycopene or an analog or derivative thereof.

[0060] The composition, kit, use, or method of the any one of the preceding clauses wherein the virus is an enveloped virus.

[0061] The composition, kit, use, or method of any one of the preceding clauses wherein the virus is a RNA virus.

[0062] The composition, kit, use, or method of any one of the preceding clauses wherein the virus is a positive-sense virus.

[0063] The composition, kit, use, or method of any one of the preceding clauses wherein the virus is a single stranded virus.

[0064] The composition, kit, use, or method of any one of the preceding clauses wherein the virus is a Coronaviridae.

[0065] The composition, kit, use, or method of any one of the preceding clauses wherein the virus is a Orthocoronavirinae.

[0066] The composition, kit, use, or method of any one of the preceding clauses wherein the virus uses, at least in part, host cell ACE2 receptors for entry.

[0067] The composition, kit, use, or method of any one of the preceding clauses wherein the virus uses, at least in part, host cell serine protease, such as TMPRSS2, for entry and/or infection.

[0068] In each of the foregoing and each of the following embodiments, unless otherwise indicated, it is also to be understood that the formulae include and represent any and all crystalline forms, partially crystalline forms, and non-crystalline and/or amorphous forms of the compounds.

[0069] In each of the foregoing and each of the following embodiments, unless otherwise indicated, it is also to be understood that the transitional phrase “consisting essentially of” means that the scope of the corresponding composition, kit, method, or use is to be interpreted to encompass the specified recited compounds and materials and/or steps, and also optionally include additional compounds and materials and/or steps those that do not materially affect the basic and novel characteristics of the claimed invention.

[0070] Illustrative derivatives include, but are not limited to, both those compounds that may be synthetically prepared from the compounds described herein, as well as those compounds that may be prepared in a similar way as those described herein, but differing in the selection of starting materials. It is to be understood that such derivatives may include prodrugs of the compounds described herein, compounds described herein that include one or more protection or protecting groups, including compounds that are used in the preparation of other compounds described herein.

[0071] The compounds described herein may contain one or more chiral centers, or may otherwise be capable of existing as multiple stereoisomers. It is to be understood that in one embodiment, the invention described herein is not limited to any particular stereochemical requirement, and that the compounds, and compositions, methods, uses, and medicaments that include them may be optically pure, or may be any of a variety of stereoisomeric mixtures, including racemic and other mixtures of enantiomers, other mixtures of diastereomers, and the like. It is also to be understood that such mixtures of stereoisomers may include a single stereochemical configuration at one or more chiral centers, while including mixtures of stereochemical configuration at one or more other chiral centers.

[0072] Similarly, the compounds described herein may include geometric centers, such as cis, trans, E, and Z double bonds. It is to be understood that in another embodiment, the invention described herein is not limited to any particular geometric isomer requirement, and that the compounds, and compositions, methods, uses, and medicaments that include them may be pure, or may be any of a variety of geometric isomer mixtures. It is also to be understood that such mixtures of geometric isomers may include a single configuration at one or more double bonds, while including mixtures of geometry at one or more other double bonds.

[0073] It is to be understood that in every instance disclosed herein, the recitation of a range of integers for any variable describes the recited range, every individual member in the range, and every possible subrange for that variable. For example, the recitation that n is an integer from 0 to 8, describes that range, the individual and selectable values of 0, 1, 2, 3, 4, 5, 6, 7, and 8, such as n is 0, or n is 1, or n is 2, etc. In addition, the recitation that n is an integer from 0 to 8 also describes each and every subrange, each of which may for the basis of a further embodiment, such as n is an integer from 1 to 8, from 1 to 7, from 1 to 6, from 2 to 8, from 2 to 7, from 1 to 3, from 2 to 4, etc.

[0074] As used herein, the term “composition” generally refers to any product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. It is to be understood that the compositions described herein may be prepared from isolated compounds described herein or from salts, solutions, hydrates, solvates, and other forms of the compounds described herein. It is also to be understood that the compositions may be prepared from various amorphous, non-amorphous, partially crystalline, crystalline, and/or other morphological forms of the compounds described herein. It is also to be understood that the compositions may be prepared from various hydrates and/or solvates of the compounds described herein. Accordingly, such pharmaceutical compositions that recite compounds described herein are to be understood to include each of, or any combination of, the various morphological forms and/or solvate or hydrate forms of the compounds described herein. In addition, it is to be understood that the compositions may be prepared from various co-crystals of the compounds described herein.

[0075] Illustratively, compositions may include one or more carriers, diluents, and/or excipients. The compounds described herein, or compositions containing them, may be formulated in a therapeutically effective amount in any conventional dosage forms appropriate for the methods described herein. The compounds described herein, or compositions containing them, including such formulations, may be administered by a wide variety of conventional routes for the methods described herein, and in a wide variety of dosage formats, utilizing known procedures (see generally, Remington: The Science and Practice of Pharmacy, (21.sup.st ed., 2005)).

[0076] The term “therapeutically effective amount” as used herein, refers to that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. In one aspect, the therapeutically effective amount is that which may treat or alleviate the disease or symptoms of the disease at a reasonable benefit/risk ratio applicable to any medical treatment. However, it is to be understood that the total daily usage of the compounds and compositions described herein may be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically-effective dose level for any particular patient will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, gender and diet of the patient: the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidentally with the specific compound employed; and like factors well known to the researcher, veterinarian, medical doctor or other clinician of ordinary skill.

[0077] It is also appreciated that the therapeutically effective amount, whether referring to monotherapy or combination therapy, is advantageously selected with reference to any toxicity, or other undesirable side effect, that might occur during administration of one or more of the compounds described herein. Further, it is appreciated that the co-therapies described herein may allow for the administration of lower doses of compounds that show such toxicity, or other undesirable side effect, where those lower doses are below thresholds of toxicity or lower in the therapeutic window than would otherwise be administered in the absence of a cotherapy.

[0078] In addition to the illustrative dosages and dosing protocols described herein, it is to be understood that an effective amount of any one or a mixture of the compounds described herein can be readily determined by the attending diagnostician or physician by the use of known techniques and/or by observing results obtained under analogous circumstances. In determining the effective amount or dose, a number of factors are considered by the attending diagnostician or physician, including, but not limited to the species of mammal, including human, its size, age, and general health, the specific disease or disorder involved, the degree of or involvement or the severity of the disease or disorder, the response of the individual patient, the particular compound administered, the mode of administration, the bioavailability characteristics of the preparation administered, the dose regimen selected, the use of concomitant medication, and other relevant circumstances.

[0079] The dosage of each compound of the claimed combinations depends on several factors, including: the administration method, the condition to be treated, the severity of the condition, whether the condition is to be treated or prevented, and the age, weight, and health of the person to be treated. Additionally, pharmacogenomic (the effect of genotype on the pharmacokinetic, pharmacodynamic or efficacy profile of a therapeutic) information about a particular patient may affect the dosage used.

[0080] It is to be understood that in the methods described herein, the individual components of a co-administration, or combination can be administered by any suitable means, contemporaneously, simultaneously, sequentially, separately or in a single pharmaceutical formulation. Where the co-administered compounds or compositions are administered in separate dosage forms, the number of dosages administered per day for each compound may be the same or different. The compounds or compositions may be administered via the same or different routes of administration. The compounds or compositions may be administered according to simultaneous or alternating regimens, at the same or different times during the course of the therapy, concurrently in divided or single forms.

[0081] The term “administering” as used herein includes all means of introducing the compounds and compositions described herein to the host animal, including, but are not limited to, oral (po), intravenous (iv), intramuscular (im), subcutaneous (sc), transdermal, inhalation, buccal, ocular, sublingual, vaginal, rectal, and the like. The compounds and compositions described herein may be administered in unit dosage forms and/or formulations containing conventional nontoxic pharmaceutically-acceptable carriers, adjuvants, and/or vehicles.

[0082] In making the pharmaceutical compositions of the compounds described herein, a therapeutically effective amount of one or more compounds in any of the various forms described herein may be mixed with one or more excipients, diluted by one or more excipients, or enclosed within such a carrier which can be in the form of a capsule, sachet, paper, or other container. Excipients may serve as a diluent, and can be solid, semi-solid, or liquid materials, which act as a vehicle, carrier or medium for the active ingredient. Thus, the formulation compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. The compositions may contain anywhere from about 0.1% to about 99.9% active ingredients, depending upon the selected dose and dosage form.

[0083] Caplacizumab is a novel monoclonal antibody targeting vWF that is approved for the treatment of TTP and thrombosis. Caplacizumab targets the A1-domain of vWF, inhibiting the interaction between vWF and platelets providing a sustained suppression of the vWF activity (Sargentini-Maier et al, 2019). Without being bound by theory, it is believed herein that by inhibiting the vWF-platelet glycoprotein-Ib interaction, caplacizumab blocks the adhesion of platelets to vWF multimers preventing the formation of the pathological microthrombi, and thus preventing end-organ ischemic damage. As the imbalance between vWF and ADAMTS13 is asserted herein to be a potential cause of the micro-thrombotic events seen in severe COVID-19, caplacizumab is useful for providing management of the thrombotic complications in COVID-19 patients.

[0084] Case studies in patients showing milder symptoms of diseases caused by SARS-CoV have shown that these patients mount a robust adaptive immune response as there seems to be a recruitment of immune cell populations (antibody-secreting cells, follicular helper T cells and activated CD4+ and CD8+ T cells) before the resolution of symptoms. Without being bound by theory, it is believed herein that those immune parameters may be exploited in order to confer protection against the virus and help alleviate the inflammatory state seen in COVID-19 patients because the viral infection in COVID-19 patients may also progress in hyper-inflammation and cytokine release syndrome (CRS), also referred to as a cytokine storm. Therefore, without being bound by theory, it is also believed herein that irbesartan is therapeutically effective by at least conferring potent anti-inflammatory and anti-fibrotic properties that will reduce the potential for a cytokine storm common to viral diseases, such as COVID-19.

[0085] In addition, SARS-CoV-2 infection has been shown to proceed into acute respiratory distress syndrome (ARDS) with the simultaneous down-regulation of ACE2. (Ferrario et al, 2005) (Gu et al, 2016) (Kuba et al, 2005). Irbesartan, (Aprovel, Karvea, Avapro et al.) is a generic oral medication approved for the treatment of high blood pressure, heart failure, and diabetic kidney disease. Irbesartan is a potent ARB inhibitor that is typically prescribed for the initial management of hypertension. Without being bound by theory, it is believed herein that irbesartan is therapeutically effective by at least up-regulating ACE2. Therefore, the up-regulation of ACE2 that degrades angiotensin II to angiotensin, is believed to improve outcomes in ARDS, SARS, COVID19, and related diseases.

[0086] The effective use of the compounds, compositions, and methods described herein for treating or ameliorating one or more effects of a viral infection using one or more compounds described herein may be based upon animal models, such as murine, canine, porcine, and non-human primate animal models of disease.

[0087] The following examples further illustrate specific embodiments of the invention; however, the following illustrative examples should not be interpreted in any way to limit the invention.

EXAMPLES

[0088] EXAMPLE. Viral RNA replication in vitro assay. Using a conventional qPCR and/or RT-qPCR assay for RNA expression, for example, commercially available assays from Promega, the compounds and compositions described herein show knock-down of viral RNA expression and signaling.

[0089] EXAMPLE. Viral infection in vitro assay. Using a conventional assay for viral infection and host cell entry, for example in monkey or human cells, the compounds and compositions described herein show delayed and/or decreased infection. Briefly, human bronchial epithelial cells, such as Calu-3 cells, are evaluated as described by Beaulieu A. et al. J Virol. 2013 April; 87(8):4237-51. Calu-3 cells are washed with Dulbecco's phosphate-buffered saline (D-PBS) and exposed to test virus strains (diluted in incomplete medium; 0.2% bovine serum albumin [BSA] instead of FBS). After virus adsorption (1 h at 37° C.), cells are washed once with D-PBS, and then incubated in incomplete culture medium containing increasing concentrations of one or more compounds or compositions described herein for 48 h. viral titers may be determined in the supernatants of infected cells by any conventional method, such as by using a viral plaque assay.

[0090] EXAMPLE. Viral infection in vitro assay. Using a conventional assay for cell survival, the compounds and compositions described herein show increased cell survival in the presence of replicating virus compared to untreated control cells.

[0091] EXAMPLE. Viral infection in vivo assay. Host animals, such as mice (for example, female or male BALB/c mice 8-10 weeks old (Jackson Laboratory, Bar Harbor, Me.), rats, or monkeys are exposed to viral particles. Host animals are separated in treatment and untreated control groups. Compounds and compositions described herein are administered to the treatment groups are various doses. Host animals are assessed for viral load after a predetermined period of time. The compounds and compositions described herein show decreased viral load in a dose dependent manner compared to control animals.

[0092] The following publications, and each of the additional publications cited herein are incorporated herein by reference:

[0093] Zhou P, Yang X L, Wang X G, Hu B, Zhang L, Zhang W, Si H R, Zhu Y, Li B, Huang C L, Chen H D, Chen J, Luo Y, Guo H, Jiang R D, Liu M Q, Chen Y, Shen X R, Wang X, Zheng X S, Zhao K, Chen Q J, Deng F, Liu L L, Yan B, Zhan F X, Wang Y Y, Xiao G F, Shi Z L. 2020. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. March; 579(7798):270-273.

[0094] Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. 2020. Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2. Science. March 4. pii: eabb2762.

[0095] Ruan Q, Yang K, Wang W, Jiang L, Song J. 2020. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan China. Intensive Care Med. March 3. doi: 10.1007/s00134-020-05991-x.

[0096] Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens T S, Herrler G, Wu N H, Nitsche A, Müller M A, Drosten C, Pöhlmann S. 2020. Cell. March 4. pii: 50092-8674(20)30229-4.

[0097] Wang Y, Shang J, Graham R, Baric R. S, Li F. 2020. Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus Journal of Virology March, 94 (7) e00127-20.

[0098] Gembardt F, Sterner-Kock A, Imboden H, Spalteholz M, Reibitz F, Schultheiss H P, Siems W E, Walther T. 2005. Organ-specific distribution of ACE2 mRNA and correlating peptidase activity in rodents. Peptides. July; 26(7):1270-7.

[0099] Soler M J, Barrios C, Oliva R, Batlle D. 2008. Pharmacologic modulation of ACE2 expression. Curr Hypertens Rep. October; 10(5):410-4.

[0100] Hamming I, Timens W, Bulthuis M L, Lely A T, Navis G, van Goor H. 2004. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. June; 203(2):631-7.

[0101] Santos R A, Simoes e Silva A C, Maric C, Silva D M, Machado R P, de Buhr I, Heringer-Walther S, Pinheiro S V, Lopes M T, Bader M, Mendes E P, Lemos V S, Campagnole-Santos M J, Schultheiss H P, Speth R, Walther T. 2003. Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci USA. July 8; 100(14):8258-63.

[0102] Chamsi-Pasha M A, Shao Z, Tang W H. 2014. Angiotensin-converting enzyme 2 as a therapeutic target for heart failure. Curr Heart Fail Rep. March; 11(1):58-63.

[0103] Ishiyama Y, Gallagher P E, Averill D B, Tallant E A, Brosnihan K B, Ferrario C M. 2004. Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors. Hypertension. May; 43(5):970-6.

[0104] Klimas J, Olvedy M, Ochodnicka-Mackovicova K, Kruzliak P, Cacanyiova S, Kristek F, Krenek P, Ochodnicky P. 2015. Perinatally administered losartan augments renal ACE2 expression but not cardiac or renal Mas receptor in spontaneously hypertensive rats. J Cell Mol Med. August; 19(8):1965-74.

[0105] Furuhashi M, Moniwa N, Mita T, Fuseya T, Ishimura S, Ohno K, Shibata S, Tanaka M, Watanabe Y, Akasaka H, Ohnishi H, Yoshida H, Takizawa H, Saitoh S, Ura N, Shimamoto K, Miura T. 2015. Urinary angiotensin-converting enzyme 2 in hypertensive patients may be increased by olmesartan, an angiotensin II receptor blocker. Am J Hypertens. January; 28(1):15-21.

[0106] Imai Y, Kuba K, Rao S, Huan Y, Guo F, Guan B, Yang P, Sarao R, Wada T, Leong-Poi H, Crackower M A, Fukamizu A, Hui C C, Hein L, Uhlig S, Slutsky A S, Jiang C, Penninger J M. 2005. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. July 7;436(7047):112-6.

[0107] Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, Huan Y, Yang P, Zhang Y, Deng W, Bao L, Zhang B, Liu G, Wang Z, Chappell M, Liu Y, Zheng D, Leibbrandt A, Wada T, Slutsky AS, Liu D, Qin C, Jiang C, Penninger J M. 2005. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. August; 11(8):875-9.

[0108] Esler M, Esler D. 2020. Can angiotensin receptor-blocking drugs perhaps be harmful in the COVID-19 pandemic? J Hypertens. March 11.

[0109] Fang L, Karakiulakis G, Roth M. 2020. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med.

[0110] Kawase M, Shirato K, van der Hoek L,Taguchi F, Matsuyama S. 2012. Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry. J Virol. June; 86(12): 6537-45.

[0111] Hayashi T, Hotta H Itoh M Homma M. 1991. Protection of mice by a protease inhibitor, aprotinin, against lethal Sendai virus pneumonia. J Gen Virol April; 72 (Pt 4):979-82.

[0112] Thevarajan, I., Nguyen, T. H. O., Koutsakos, M. et al. 2020. Breadth of concomitant immune responses prior to patient recovery: a case report of non-severe COVID-19. Nat Med. https://doi.org/10.1038/s41591-020-0819-2

[0113] Mehta P, McAuley D F, Brown M, Sanchez E, Tattersall R S, Manson J J, HLH Across Speciality Collaboration, UK. 2020. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet March 16. pii: S0140-6736(20)30628-0. doi: 10.1016/S0140-6736(20)30628-0.

[0114] Yamaya M1, Shimotai Y2, Hatachi Y3, Lusamba Kalonji N4, Tando Y, Kitajima Y, Matsuo K, Kubo H, Nagatomi R, Hongo S, Homma M, Nishimura H. 2015. The serine protease inhibitor camostat inhibits influenza virus replication and cytokine production in primary cultures of human tracheal epithelial cells. Pulm Pharmacol Ther. August; 33:66-74. doi: 10.1016/j.pupt.2015.07.001.

[0115] Iwata-Yoshikawa N, Okamura T, Shimizu Y, Hasegawa H, Takeda M, Nagata N. 2019. TMPRSS2 Contributes to Virus Spread and Immunopathology in the Airways of Murine Models after Coronavirus Infection. J Virol. March 5; 93(6).

[0116] Shen L W, Mao H J, Wu Y L, Tanaka Y, Zhang W. 2017. TMPRSS2: A potential target for treatment of influenza virus and coronavirus infections. Biochimie. November; 142:1-10. doi: 10.1016/j.biochi.2017.07.016.

[0117] Tanaka J, Tajima S, Asakawa K, Sakagami T, Moriyama H, Takada T, Suzuki E, Narita I. 2013. Preventive effect of irbesartan on bleomycin-induced lung injury in mice. Respir Investig. June; 51(2):76-83.

[0118] Ferrario C M, Jessup J, Chappell M C, Averill D B, Brosnihan K B, Tallant E A, Diz D I, Gallagher P E. 2005. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation; 111:2605-2610.

[0119] Gu H, Xie Z, Li T, Zhang S, Lai C, Zhu P, Wang K, Han L, Duan Y, Zhao Z, et al. 2016. Angiotensin-converting enzyme 2 inhibits lung injury induced by respiratory syncytial virus. Sci Rep.; 6:19840.