EP4243805A1

EP4243805A1 - Combination therapies for treating coronavirus infection

Info

Publication number: EP4243805A1
Application number: EP21762002.0A
Authority: EP
Inventors: Daniel Joseph Fitzgerald
Original assignee: Gbiotech Sarl
Current assignee: Halo Therapeutics Ltd
Priority date: 2020-08-07
Filing date: 2021-08-06
Publication date: 2023-09-20
Also published as: WO2022029334A1

Abstract

The present invention relates to therapeutic drug combinations particularly useful for treatment and/or prevention of coronavirus infection. Said therapeutics combinations are focused primarily on small molecule drugs that impact lipidomic systems, metabolomic systems, immunomodulary and inflammatory systems. A further aspect of the invention relates to methods for treating coronavirus infection using said therapeutics combinations.

Description

Combination therapies for treating coronavirus infection

The present invention is, at least in part, based on the following background:

SARS-CoV-2 and other human coronaviruses. Key to SARS-CoV-2 therapeutic development is a better understanding of the mechanisms which drive its high infectivity, unusually broad tissue tropism and severe pathology (1 ,2,3). At present, there are seven coronaviruses that are known to infect humans. The four endemic human coronaviruses OC43, 229E, HKLI1, and NL63 cause mild, self-limiting upper respiratory tract infections while pandemic virus SARS-CoV-2, and earlier SARS-CoV and MERS-CoV can cause severe pneumonia with acute respiratory distress syndrome, multi-organ failure, and death (3,5). In order to enable development of effective therapeutic interventions, a central goal of ongoing research into the COVID-19 pandemic is to determine the features of SARS-CoV-2 that distinguish it from predecessor coronaviruses and provide it with a lethal combination of high infectivity and high pathogenicity.

SARS-CoV-2 pathology. COVID-19 patients display an odd collection of symptoms not seen with any previous human coronavirus including blood clots, strokes, “COVID toes” and heart attacks (6,7,8). While SARS-CoV did not significantly spread past the lungs, a recent study reported damage or severe inflammation in SARS-CoV-2 patients’ endothelial cells in the heart, kidneys, liver, and intestines, suggestive of a vascular infection rather than a respiratory disease (1). While this significantly expanded tissue tropism might be partially explained by more widespread and effective spike glycoprotein processing systems (9,10,11), the accompanying severe immune dysregulation, inflammation and tissue pathology both inside and outside of the lungs remains poorly understood. Receptor recognition and cell entry by SARS-CoV-2. Receptor recognition by coronaviruses is an important determinant of viral infectivity and pathogenesis, and represents a major target for antiviral therapeutic development (12). The attachment of SARS-CoV-2 to a host cell is initiated by interactions between the spike (S) glycoprotein and its cognate receptor angiotensin-converting enzyme 2 (ACE2) which are higher affinity than with previous closely related SARS-CoV and also other human coronaviruses (9,13,14). Following receptor docking by SARS-CoV-2 and prior to membrane fusion, the S glycoprotein can be processed by a plasma membrane-associated protease, TMPRSS2, which helps to unload virus components into the host cell cytoplasm (9,10). Once inside the host cell, human coronaviruses including the mild endemic species have evolved systems to evade the innate immune system (15,16) and remodel its lipid metabolism to facilitate virus replication (4). SARS-CoV-2 has acquired additional novel functions that characterize its harsh disease phenotype. Relative to other human coronaviruses SARS-CoV-2 exhibits more effective protease processing (10,11), and a broader cell tropism to drive rapid unloading of virus into diverse tissues (1 ,17). A novel S1/S2 polybasic furin protease cleavage site stimulates cell-cell fusion and entry into host cells (11).

Dysregulated immune response and inflammation triggered by SARS-CoV-2 infection. Infection by SARS-CoV-2 also triggers an unusually impaired and dysregulated immune response (18) and a heightened inflammatory response (2). Hyper-immunity and inflammatory responses of the host to SARS-CoV-2 work in synergy with interferon production in the vicinity of infected cells to drive a feed-forward loop to upregulate ACE2 and further escalate infection (19).

Structure of the SARS-CoV-2 S glycoprotein as visualized by cryo-EM. In the search for additional novel functions that contribute to the observed extreme pathology of infection, we recently disclosed the structure of the SARS-CoV-2 S glycoprotein by cryo-EM and discovered in our structure that each S in the trimer tightly binds one copy of linoleic acid (20). The presence of linoleic acid (hereinafter referred to as “LA”) had not been previously disclosed in any crystal structures or cryo-EM structures of coronavirus S proteins. LA is a polyunsaturated omega-6 fatty acid and is one of two essential fatty acids for humans, who must obtain it through their diet. It is a colorless or white oil that is virtually insoluble in water. Via analysis of available crystal structures and cryo-EM structures, we found four molecular features mediating LA binding to SARS-CoV-2, are also present in the S proteins of the pathogenic coronaviruses SARS-CoV and MERS-CoV: i) a conserved hydrophobic pocket; ii) a gating helix; iii) amino acid residues pre-positioned to interact with the LA carboxy headgroup; and iv) loosely packed RBDs in the ‘apo’ form (where ‘apo’ means S proteins without bound LA). Critically, in each of the four pathologically mild, endemic human coronaviruses, one or more of these four architectural prerequisites mediating LA binding are lacking in the respective S protein structures. Furthermore, we demonstrated via cryo-EM that conformational changes in the RBD trimer triggered by LA binding impact ACE2 docking, and therefore infectivity. The S protein's highly selective binding of LA originates from the very well-defined size and shape complementarity afforded by the LA-binding pocket, which is supported by the observation that we only detected LA in our analyses, and not other free fatty acids, even though hundreds of distinct free fatty acids (FFAs) were present in the culture media and the cultured cells where the S protein was produced. Interestingly, exogenous supplement of LA or AA suppressed coronavirus replication (4). It is remarkable in this context that the S trimer of SARS-CoV-2 binds LA with astonishing specificity, endowing a scavenger function on S, poised to impact lipid remodeling and fuel SARS-CoV- 2 pathologies

Biological implications of LA binding to SARS-CoV-2 S protein, and depletion of LA from cells. A recent proteomic and metabolomic study of COVID-19 patient sera evidenced continuous decrease of FFAs including LA (21). Lipid metabolome remodeling is a common element of viral infection (22,23,24). For coronaviruses, the LA to arachidonic acid (AA) metabolism axis was identified as the epicenter of lipid remodeling (4). A recent study by Ehrlich, et al. (25) investigated the entire transcriptional landscape accompanying SARS- CoV-2 of lung epithelial cells. Ehrlich, et al. (25) likewise revealed a central focus by SARS- CoV-2 on disrupting the lipid metabalome and demonstrated that infection upregulates lipogenesis and cholesterol synthesis genes in primary bronchial epithelial cells, and differentially up-regulates both HMG-CoA synthase and squalene monooxygenase, which are rate-limiting steps in cholesterol synthesis. Ehrlich, et al. (25) further identified small molecule therapeutics presently employed by the medical community to combat dyslipidaemias and metabolic disorders as being of potential use in treating coronavirus infection.

Since the binding of LA to its pocket in the Spike protein lowers infectivity via conformational changes, exogenous supplement of LA or AA suppresses coronavirus replication, and infection of coronaviruses in general disrupts lipid metabolism, it is therefore one object of this invention to provide material compositions and methods for therapeutic interventions which include combinations of LA, or derivative or mimetics of LA together in combination with therapeutics known to impact lipid metabolism, or lipid metabolome remodeling. Lipid metabolome remodeling alters three separate processes in cells (4,22,23):

(i) energy homeostasis via changes in catabolic and anabolic precursor equilibria; It is therefore a second object of this invention to provide material compositions and methods for therapeutic interventions which modulate or energy homeostasis via changes in catabolic and anabolic precursor equilibria in coronavirus infected cells.

(ii) fluidity and elasticity of biological membranes, via e.g. changes in the saturated to unsaturated fatty acid ratio in phospholipids; Regarding the potential impact of LA axis remodeling on fluidity and elasticity of biological membranes, we note that the FFA composition of phospholipid bilayers is a key element in maintaining surface tension in lungs, and alteration of LA axis lipid composition is observed in acute respiratory distress syndrome and severe pneumonia, both of which are key symptoms of SARS- CoV-2 infection. It is therefore a third object of this invention to provide material compositions and methods for therapeutic interventions which modulate or stabilize the fluidity and elasticity of biological membranes in coronavirus infected cells

(iii) cell signaling, via changes in levels of lipid-based cell signaling precursors. Significant changes in cell signalling are anticipated due to LA to AA metabolome axis remodelling, since the LA biosynthetic pathway leads to eicosanoids, which are prominent signalling molecules involved in inflammatory processes (26). We previously disclosed that SARS-CoV-2 comprises a FFA-binding pocket that specifically accretes LA (20), and provided evidence that this could be a feature shared with SARS-CoV and MERS-CoV. The high affinity, high specificity LA scavenger function conveyed by our results could confer a tissue-independent mechanism by which pathogenic coronavirus infection drives immune dysregulation and inflammation. Our findings also suggest that the multinodal LA signalling axis also represents excellent therapeutic intervention points against coronavirus infections, particularly in patient groups with increased risk due to metabolic preconditions, such as diabetes, or dislipidemias. It is therefore a fourth object of this invention to provide material compositions and methods for therapeutic interventions which modulate or stabilize cell signalling along the LA to AA (arachidonic acid) metabolome axis in coronavirus infected cells.

The above objects are attained by the embodiments of the present invention as defined in the claims and the present description.

In particular, the invention provides a pharmaceutical composition comprising 2 or more, preferably 2, 3, 4 or 5, more preferred 2 or 3, especially preferred 2, of the therapeutics selected from the following categories a) to w) a) linoleic acid (“LA”), a derivative, salt or mimetic thereof; b) a broad-spectrum antiviral agent (BSAA); c) a nucleoside analogue; d) a Phospholipase A2 (PLA2) inhibitor; e) a corticosteroid; f) an antibiotic; g) a peroxisome proliferator-activated receptor (PPAR) agonist; h) a protease inhibitor; i) an angiotensin-converting enzyme 2 (ACE2) receptor inhibitor/antagonist; j) a cytokine inhibitor or cytokine release inhibitor; k) a free fatty acid receptor (FFAR) agonist; l) a SGLT l/ll inhibitor/antagonist; m) a kinase inhibitor; n) an interferon; o) an interleukin; p) a lipid lowering/dislipidemia drug; q) an antihypertensive; r) a Bromodomain inhibitor; s) an anti-inflammatory; t) a pulmonary fibrosis (PF) drugs, including idiopathic pulmonary fibrosis (IPF) drugs, whereby such PF drugs are preferably selected from Nintedanib, and Pirfenidone as well as mixtures thereof; u) an anticancer drug such as preferably Selinexor, zotatifin, Plitidepsin, Pevonedistat, and mixtures of two or more thereof, v) an antihyperglycemic such as preferably ternatin-4, and w) antihistamines such as preferably haloperidol, melperone, clemastine, cloperastine, and mixtures of two or more thereof.

According to the invention, the terms “therapeutic”, “therapeutic agent”, “therapeutic drug” are used synonymously, and are sometimes also referred to as “drug”, and include, where applicable as understood by the person skilled in the art, prodrugs, pharmaceutically acceptable salts, pharmaceutally active stereoisomers, and/or racematic mixtures of such “therapeutic”, “therapeutic agent”, “therapeutic drug” or “drug”, respectively.

Therapeutics of the above categories b) to w) are also referred to herein as “non-LA therapeutics” or “non-LA therapeutic drugs” or “non-LA drugs”.

Preferred combinations of therapeutic agents according to the invention are as follows: At least one therapeutic of category a) and at least one therapeutic of category b).

At least one therapeutic of category a) and at least one therapeutic of category c).

At least one therapeutic of category a) and at least one therapeutic of category d).

At least one therapeutic of category a) and at least one therapeutic of category e).

At least one therapeutic of category a) and at least one therapeutic of category f).

At least one therapeutic of category a) and at least one therapeutic of category g).

At least one therapeutic of category a) and at least one therapeutic of category h).

At least one therapeutic of category a) and at least one therapeutic of category i).

At least one therapeutic of category a) and at least one therapeutic of category j). At least one therapeutic of category a) and at least one therapeutic of category k). At least one therapeutic of category a) and at least one therapeutic of category I). At least one therapeutic of category a) and at least one therapeutic of category m). At least one therapeutic of category a) and at least one therapeutic of category n). At least one therapeutic of category a) and at least one therapeutic of category o). At least one therapeutic of category a) and at least one therapeutic of category p). At least one therapeutic of category a) and at least one therapeutic of category q). At least one therapeutic of category a) and at least one therapeutic of category r). At least one therapeutic of category a) and at least one therapeutic of category s). At least one therapeutic of category a) and at least one therapeutic of category t). At least one therapeutic of category a) and at least one therapeutic of category u). At least one therapeutic of category a) and at least one therapeutic of category v). At least one therapeutic of category a) and at least one therapeutic of category w).

Other preferred embodiments of the invention include the following combinations of therapeutics:

At least one therapeutic of category b) and at least one therapeutic of category c).

At least one therapeutic of category b) and at least one therapeutic of category d).

At least one therapeutic of category b) and at least one therapeutic of category e).

At least one therapeutic of category b) and at least one therapeutic of category f).

At least one therapeutic of category b) and at least one therapeutic of category g).

At least one therapeutic of category b) and at least one therapeutic of category h).

At least one therapeutic of category b) and at least one therapeutic of category i).

At least one therapeutic of category b) and at least one therapeutic of category j).

At least one therapeutic of category b) and at least one therapeutic of category k).

At least one therapeutic of category b) and at least one therapeutic of category m). At least one therapeutic of category b) and at least one therapeutic of category n). At least one therapeutic of category b) and at least one therapeutic of category o).

At least one therapeutic of category b) and at least one therapeutic of category p).

At least one therapeutic of category b) and at least one therapeutic of category q).

At least one therapeutic of category b) and at least one therapeutic of category r).

At least one therapeutic of category b) and at least one therapeutic of category s).

At least one therapeutic of category b) and at least one therapeutic of category t).

At least one therapeutic of category b) and at least one therapeutic of category u).

At least one therapeutic of category b) and at least one therapeutic of category v).

At least one therapeutic of category b) and at least one therapeutic of category w).

Further preferred embodiments of the invention include the following combinations of therapeutics:

At least one therapeutic of category c) and at least one therapeutic of category d).

At least one therapeutic of category c) and at least one therapeutic of category e).

At least one therapeutic of category c) and at least one therapeutic of category f).

At least one therapeutic of category c) and at least one therapeutic of category g).

At least one therapeutic of category c) and at least one therapeutic of category h).

At least one therapeutic of category c) and at least one therapeutic of category i).

At least one therapeutic of category c) and at least one therapeutic of category j).

At least one therapeutic of category c) and at least one therapeutic of category k).

At least one therapeutic of category c) and at least one therapeutic of category m).

At least one therapeutic of category c) and at least one therapeutic of category n).

At least one therapeutic of category c) and at least one therapeutic of category o).

At least one therapeutic of category c) and at least one therapeutic of category p).

At least one therapeutic of category c) and at least one therapeutic of category q).

At least one therapeutic of category c) and at least one therapeutic of category r).

At least one therapeutic of category c) and at least one therapeutic of category s).

At least one therapeutic of category c) and at least one therapeutic of category t).

At least one therapeutic of category c) and at least one therapeutic of category u).

At least one therapeutic of category c) and at least one therapeutic of category v).

At least one therapeutic of category c) and at least one therapeutic of category w).

Still other preferred embodiments of the invention include the following combinations of therapeutics:

At least one therapeutic of category d) and at least one therapeutic of category e). At least one therapeutic of category d) and at least one therapeutic of category f). At least one therapeutic of category d) and at least one therapeutic of category g).

At least one therapeutic of category d) and at least one therapeutic of category h).

At least one therapeutic of category d) and at least one therapeutic of category i).

At least one therapeutic of category d) and at least one therapeutic of category j).

At least one therapeutic of category d) and at least one therapeutic of category k).

At least one therapeutic of category d) and at least one therapeutic of category m).

At least one therapeutic of category d) and at least one therapeutic of category n).

At least one therapeutic of category d) and at least one therapeutic of category o).

At least one therapeutic of category d) and at least one therapeutic of category p).

At least one therapeutic of category d) and at least one therapeutic of category q).

At least one therapeutic of category d) and at least one therapeutic of category r).

At least one therapeutic of category d) and at least one therapeutic of category s).

At least one therapeutic of category d) and at least one therapeutic of category t).

At least one therapeutic of category d) and at least one therapeutic of category u).

At least one therapeutic of category d) and at least one therapeutic of category v).

At least one therapeutic of category d) and at least one therapeutic of category w).

Yet further other preferred embodiments of the invention include the following combinations of therapeutics:

At least one therapeutic of category e) and at least one therapeutic of category f).

At least one therapeutic of category e) and at least one therapeutic of category g).

At least one therapeutic of category e) and at least one therapeutic of category h).

At least one therapeutic of category e) and at least one therapeutic of category i).

At least one therapeutic of category e) and at least one therapeutic of category j).

At least one therapeutic of category e) and at least one therapeutic of category k).

At least one therapeutic of category e) and at least one therapeutic of category m).

At least one therapeutic of category e) and at least one therapeutic of category n).

At least one therapeutic of category e) and at least one therapeutic of category o).

At least one therapeutic of category e) and at least one therapeutic of category p).

At least one therapeutic of category e) and at least one therapeutic of category q).

At least one therapeutic of category e) and at least one therapeutic of category r).

At least one therapeutic of category e) and at least one therapeutic of category s).

At least one therapeutic of category e) and at least one therapeutic of category t).

At least one therapeutic of category e) and at least one therapeutic of category u).

At least one therapeutic of category e) and at least one therapeutic of category v). At least one therapeutic of category e) and at least one therapeutic of category w).

Also preferred according to the invention are the following combinations of therapeutics: At least one therapeutic of category f) and at least one therapeutic of category g).

At least one therapeutic of category f) and at least one therapeutic of category h).

At least one therapeutic of category f) and at least one therapeutic of category i).

At least one therapeutic of category f) and at least one therapeutic of category j).

At least one therapeutic of category f) and at least one therapeutic of category k).

At least one therapeutic of category f) and at least one therapeutic of category m).

At least one therapeutic of category f) and at least one therapeutic of category n).

At least one therapeutic of category f) and at least one therapeutic of category o).

At least one therapeutic of category f) and at least one therapeutic of category p).

At least one therapeutic of category f) and at least one therapeutic of category q).

At least one therapeutic of category f) and at least one therapeutic of category r).

At least one therapeutic of category f) and at least one therapeutic of category s).

At least one therapeutic of category f) and at least one therapeutic of category t).

At least one therapeutic of category f) and at least one therapeutic of category u).

At least one therapeutic of category f) and at least one therapeutic of category v).

At least one therapeutic of category f) and at least one therapeutic of category w).

Other preferred combinations of therapeutics according to the invention are as follows: At least one therapeutic of category g) and at least one therapeutic of category h). At least one therapeutic of category g) and at least one therapeutic of category i). At least one therapeutic of category g) and at least one therapeutic of category j). At least one therapeutic of category g) and at least one therapeutic of category k). At least one therapeutic of category g) and at least one therapeutic of category I). At least one therapeutic of category g) and at least one therapeutic of category m). At least one therapeutic of category g) and at least one therapeutic of category n). At least one therapeutic of category g) and at least one therapeutic of category o). At least one therapeutic of category g) and at least one therapeutic of category p). At least one therapeutic of category g) and at least one therapeutic of category q). At least one therapeutic of category g) and at least one therapeutic of category r). At least one therapeutic of category g) and at least one therapeutic of category s). At least one therapeutic of category g) and at least one therapeutic of category t). At least one therapeutic of category g) and at least one therapeutic of category u). At least one therapeutic of category g) and at least one therapeutic of category v). At least one therapeutic of category g) and at least one therapeutic of category w).

Yet other preferred combinations of therapeutics according to the invention are as follows: At least one therapeutic of category h) and at least one therapeutic of category i). At least one therapeutic of category h) and at least one therapeutic of category j). At least one therapeutic of category h) and at least one therapeutic of category k). At least one therapeutic of category h) and at least one therapeutic of category I). At least one therapeutic of category h) and at least one therapeutic of category m). At least one therapeutic of category h) and at least one therapeutic of category n). At least one therapeutic of category h) and at least one therapeutic of category o). At least one therapeutic of category h) and at least one therapeutic of category p). At least one therapeutic of category h) and at least one therapeutic of category q). At least one therapeutic of category h) and at least one therapeutic of category r). At least one therapeutic of category h) and at least one therapeutic of category s). At least one therapeutic of category h) and at least one therapeutic of category t). At least one therapeutic of category h) and at least one therapeutic of category u). At least one therapeutic of category h) and at least one therapeutic of category v). At least one therapeutic of category h) and at least one therapeutic of category w).

Further preferred according to the invention are the following combinations of therapeutics: At least one therapeutic of category i) and at least one therapeutic of category j).

At least one therapeutic of category i) and at least one therapeutic of category k).

At least one therapeutic of category i) and at least one therapeutic of category I).

At least one therapeutic of category i) and at least one therapeutic of category m).

At least one therapeutic of category i) and at least one therapeutic of category n).

At least one therapeutic of category i) and at least one therapeutic of category o).

At least one therapeutic of category i) and at least one therapeutic of category p).

At least one therapeutic of category i) and at least one therapeutic of category q).

At least one therapeutic of category i) and at least one therapeutic of category r).

At least one therapeutic of category i) and at least one therapeutic of category s).

At least one therapeutic of category i) and at least one therapeutic of category t).

At least one therapeutic of category i) and at least one therapeutic of category u).

At least one therapeutic of category i) and at least one therapeutic of category v).

At least one therapeutic of category i) and at least one therapeutic of category w).

In other preferred embodiments of the invention, preferred combinations of therapeutics are as follows: At least one therapeutic of category j) and at least one therapeutic of category k).

At least one therapeutic of category j) and at least one therapeutic of category I).

At least one therapeutic of category]) and at least one therapeutic of category m).

At least one therapeutic of category]) and at least one therapeutic of category n).

At least one therapeutic of category j) and at least one therapeutic of category o).

At least one therapeutic of category j) and at least one therapeutic of category p).

At least one therapeutic of category j) and at least one therapeutic of category q).

At least one therapeutic of category]) and at least one therapeutic of category r).

At least one therapeutic of category j) and at least one therapeutic of category s).

At least one therapeutic of category j) and at least one therapeutic of category t).

At least one therapeutic of category]) and at least one therapeutic of category u).

At least one therapeutic of category]) and at least one therapeutic of category v).

At least one therapeutic of category j) and at least one therapeutic of category w).

Still further preferred combinations of therapeutics according to the invention are as follows:

At least one therapeutic of category k) and at least one therapeutic of category I).

At least one therapeutic of category k) and at least one therapeutic of category m).

At least one therapeutic of category k) and at least one therapeutic of category n).

At least one therapeutic of category k) and at least one therapeutic of category o).

At least one therapeutic of category k) and at least one therapeutic of category p).

At least one therapeutic of category k) and at least one therapeutic of category q).

At least one therapeutic of category k) and at least one therapeutic of category r).

At least one therapeutic of category k) and at least one therapeutic of category s).

At least one therapeutic of category k) and at least one therapeutic of category t).

At least one therapeutic of category k) and at least one therapeutic of category u).

At least one therapeutic of category k) and at least one therapeutic of category v).

At least one therapeutic of category k) and at least one therapeutic of category w).

Yet other preferred combinations of therapeutics according to the invention are as follows:

At least one therapeutic of category I) and at least one therapeutic of category t). At least one therapeutic of category I) and at least one therapeutic of category u).

The invention is also preferably directed to the following combinations of therapeutics: At least one therapeutic of category m) and at least one therapeutic of category n).

At least one therapeutic of category m) and at least one therapeutic of category o).

At least one therapeutic of category m) and at least one therapeutic of category p).

At least one therapeutic of category m) and at least one therapeutic of category q).

At least one therapeutic of category m) and at least one therapeutic of category r).

At least one therapeutic of category m) and at least one therapeutic of category s).

At least one therapeutic of category m) and at least one therapeutic of category t).

At least one therapeutic of category m) and at least one therapeutic of category u).

At least one therapeutic of category m) and at least one therapeutic of category v).

At least one therapeutic of category m and at least one therapeutic of category w).

Furthermore, the invention is preferably directed to the following combinations of therapeutics:

At least one therapeutic of category n) and at least one therapeutic of category o).

At least one therapeutic of category n) and at least one therapeutic of category p).

At least one therapeutic of category n) and at least one therapeutic of category q).

At least one therapeutic of category n) and at least one therapeutic of category r).

At least one therapeutic of category n) and at least one therapeutic of category s).

At least one therapeutic of category n) and at least one therapeutic of category t).

At least one therapeutic of category o) and at least one therapeutic of category p).

At least one therapeutic of category o) and at least one therapeutic of category q).

At least one therapeutic of category o) and at least one therapeutic of category r).

At least one therapeutic of category o) and at least one therapeutic of category s).

At least one therapeutic of category o) and at least one therapeutic of category t).

At least one therapeutic of category o) and at least one therapeutic of category u).

At least one therapeutic of category o) and at least one therapeutic of category v).

At least one therapeutic of category o) and at least one therapeutic of category w). Other preferred embodiments of the invention include the following combinations of therapeutics:

At least one therapeutic of category p) and at least one therapeutic of category q).

At least one therapeutic of category p) and at least one therapeutic of category r).

At least one therapeutic of category p) and at least one therapeutic of category s).

At least one therapeutic of category p) and at least one therapeutic of category t).

At least one therapeutic of category p) and at least one therapeutic of category u).

At least one therapeutic of category p) and at least one therapeutic of category v).

At least one therapeutic of category p) and at least one therapeutic of category w).

Still further preferred embodiments of the invention include the following combinations of therapeutics:

At least one therapeutic of category q) and at least one therapeutic of category r). At least one therapeutic of category q) and at least one therapeutic of category s). At least one therapeutic of category q) and at least one therapeutic of category t).

At least one therapeutic of category q) and at least one therapeutic of category u).

At least one therapeutic of category q) and at least one therapeutic of category v). At least one therapeutic of category w) and at least one therapeutic of category w).

Also preferred according to the invention are the following combinations of therapeutics: At least one therapeutic of category r) and at least one therapeutic of category s).

At least one therapeutic of category r) and at least one therapeutic of category t).

Further preferred embodiments of the invention are the following combinations of therapeutics:

At least one therapeutic of category s) and at least one therapeutic of category t). At least one therapeutic of category s) and at least one therapeutic of category u). At least one therapeutic of category s) and at least one therapeutic of category v). At least one therapeutic of category s) and at least one therapeutic of category w).

Still other preferred embodiments are the following combinations of therapeutics: At least one therapeutic of category t) and at least one therapeutic of category u). At least one therapeutic of category t) and at least one therapeutic of category v). At least one therapeutic of category t) and at least one therapeutic of category w).

Yet other preferred embodiments of the invention are provided by the following combinations of therapeutics: At least one therapeutic of category u) and at least one therapeutic of category v). At least one therapeutic of category u) and at least one therapeutic of category w).

Another preferred embodiment of the invention is the following combination of therapeutics: At least one therapeutic of category v) and at least one therapeutic of category w).

According to the invention “derivative or “mimetic” of LA is generally a structure having the necessary requirements for binding to the coronavirus S protein or a fragment or mutant thereof as disclosed herein, in particular to a binding pocket of the coronavirus S protein or a fragment or mutant thereof as disclosed herein, combining at least the following structural features: at least two, preferably exactly two, basic amino acid residues, typically being directly following one another in the amino acid sequence of said coronavirus S protein or a fragment or mutant thereof as defined herein, and a tube-like cavity in the structure of said coronavirus S protein or a fragment or mutant thereof as disclosed herein formed by lipophilic acid residues. Preferably, the binding site is also composed by an alpha-helix gating said hydrophobic tube. Typical derivatives or mimetics of LA have a polar head group and an apolar extended tail group, wherein the polar head group is coordinated by said at least two, or exactly two, basic amino acid residues, and said apolar tail group fits into said hydrophobic tube.

More preferably, a derivative or mimetic of LA is characterised by the following general formula (I): wherein

Q is selected from O, S and NH, and ismost preferred O;

R1 is selected from OR, NHR3, and SH, wherein R3 is H or a short chain alkyl or substitutet alkyl group having 1 to 3 carbon atoms, and is preferably NH2 or OH, most preferred OH; and R2 is a straight unsubstituted or substituted hydrocarbyl group having from 13 to 21 C atoms, preferably 17 C atoms, optionally linked or bound to a detectable label. From the present dislosure, the skilled person is aware that the expression “a derivative or mimetic of LA” according to the invention also includes other fatty acids besides LA itself.

Preferably, the group R2 has at least one unsaturated C-C bond, more preferably two unsaturated C-C bonds. Preferably, the group R2 has 1 , 2, 3, 4 or 5 unsaturated C-C bonds. More preferably, at least one unsaturated C-C bond is between C-8 and C-9. In other preferred embodiments, at least one unsaturated C-C bond is between C-11 and C-12 of the hydrocarbyl group. Most preferred, the R2 has an unsaturated C-C bond between C-8 and C- 9 and an unsaturated C-C-bond between C-11 and C-12. It is to be understood that the above C numbering of the hydrocarbyl group is counted from the carbon bound to the C=Q group in formula (I). Preferably, the one or more unsaturated C-C- bond(s) in the hydrocarbyl groups is/are C-C double bonds.

Preferred embodiments of compounds of formula (I) (in particular fatty acids) are outlined as follows (indicated by trivial name(s) and according to the lipid number and omega-x nomenclature):

An especially preferred compound (fatty acid of formula (I)) is oleic acid (18:1 cis-9).

Another preferred compound (fatty acid of formula (I)) is arachidonic acid (20:4 (n-6); also denoted as “AA”or “ARA”).

Other preferred embedments of a compound (fatty acid of formula (I)) inclucde elaidic acid (18:1 trans-9), eicosapentaenoic acid (20:5 (n-3), stearic acid (18:0), gamma-linoleic acid (also denoted as “GLA”; 18:3 (n-6)), calendic acid (18:3 (n-6)), arachidic acid (synonym: eicosanoic acid; 20:0), and dihomo-gamma-linoleic acid (20:3 (n-6)).

Still other preferred embodiments of a compound (fatty acid of formula (I)) include docosadienoic acid (22:2 (n-6)), adrenic acid (22:4 (n-6)), palmitic acid (16:0) and behenic acid (synonym: docosanoic acid; 22:0).

According to the invention, a compound of formula (I) such as preferred compounds as outlined above include salts, anions and conjugates of such compounds (or fatty acids, respectively) as defined herein.

A “salt” of LA or generally a “salt” of a compound of formula (I), respectively, is typically an LA salt or generally a salt of a compound of formula (I), respectively, selected from the alkali metal and earth alkaline metals of the periodic system. Preferred alkaline salts of LA or generally preferred salts of a compound of formula (I), respectively, are those of sodium, kalium and lithium. Preferred earth alkaline salts of LA or generally preferred earth alkaline salts of a compound of formula (I), respectively, are those of calcium and barium. It is to be understood that the “salts” of a compond of formula (I) are preferably salts of preferred fatty acid compounds as outlined above.

A “salt” of LA according to the invention may be also or alternatively used according to the invention to refer to the anionic form of LA or its mimetics or derivatives, in particular compounds (in particular fatty acids) of formula (I), preferably those preferred embodiments as outlined above.

Broad-spectrum antiviral agents (BSAA) according to the invention are agents that at least target, i.e. inhibit, more than one virus within a family of viruses, especially preferred BSAAs for use in the invention inhibit viruses belonging to two or more viral families.

Preferred Broad-spectrum antiviral agents (BSAA) for use in the invention include, but are not limited to, Nitazoxanide, Favipiravir, Mycophenolic acid, Remdesivir, Cidofovir, Chloroquine, Niclosamide, Amodiaquine, Brincidofovir, El PA ( also known as amiloride), Emetine, BCX4430 (also known as Galidesivir), Gemcitabine, Rapamycin (also known as Sirolimus), ABT-263, Berberine, Cyclosporine (preferably Cyclosporina A), Brequinar, Obatoclax, Luteolin, Ribavirin, Tilorone (also known as Amixin), Glycyrrhizin, Eflornithine, Sorafenib, Suramin, Monensin, Arbidol (also known as Umifenovir), Sunitinib, Labyrinthopeptin A2, Silvestrol, Emodin, Amiodarone, Raloxifene, Azithromycin, Ivermectin, Labyrinthopeptin A1 , Mitoxantrone, Ganciclovir, Letermovir, Artesunate, Dasatinib, Chlorpromazine, Hydroxychloroquine, Foscarnet, Simvastatin, Bortezomib, Camptothecin, Homoharringtonine, Itraconazole, Azacitidine, Leflunomide, Nelfinavir, Valacyclovir, 4-HPR (also known as Fenretinide), Aprotinin, Topotecan, Oritavancin, Tamoxifen, Novobiocin, Pentosan polysulfate, Ezetimibe, Lopinavir, Filociclovir, Isolanid (also known as lanatoside C), Sofosbuvir, Manidipine, Anisomycin, Lovastatin, Metformin, Minocycline, Benztropine, Dalbavancin, Teicoplanin, N-MCT, Roscovitine (also known as Seliciclib), Caffeine, Genistin, Regorafenib, Alisporivir, Cepharanthine, Mefloquine, Erlotinib, Gefitinib, Hexachlorophene, Imatinib, Lobucavir, Verapamil, Apoptozole, Fluoxetine, Fluvastatin, Posaconazole, Quinacrine, Nafamostat, Teriflunomide, Aciclovir, Acetylsalicylic acid, Camostat, Memantine, Tenofovir, Dibucaine, Pirlindole, Formoterol, Pleconaril, Indomethacin, Ritonavir, Flavopiridol, Bithionol, Doxycycline, Salinomycin, Saracatinib, Bepridil, Quinine, Clomipramine, Diphyllin, Telavancin, Toremifene, Promethazine, Kasugamycin, Trametinib, Zanamivir, CYT107, Lamivudine, Thymalfasin, Atovaquone, Irbesartan, PS3061 , Alpha-lipoic acid, and mixtures of two or more thereof.

Preferred nucleoside analogues for use in the invention include, but are not limited to, deoxyadenosine analogues, adenosine analogues, deoxycytidine analogues, guanosine analogues, deoxyguanosine analogues, thymidine analogues, deoxythymidine analogues, deoxyuridine analogues, and mixtures of two or more thereof.

It is to be understood that nucleoside analogues for use in the invention are typically antiviral agents, and may be BSAAs. The person skilled in the art is readily able to differentiate nucleoside analogues which inhibit only one virus (or one family of viruses) and nucleoside analogues for use in the invention which inhibit viruses of two or more virus families.

Specific preferred examples of nucleoside analogues for use in the invention include, but are not limited to abacavir, aciclovir, cytarabine, didanosine, emtricitabine, entecavir, favipiravir, galidesivir, gemcitabine, idoxuridine, lamivudine, remdesivir, ribavirin, stavudine, taribavirin, telbivudine, trifluridine, vidarabine, zalcitabine, zidovudine, and mixtures of two or more thereof

Preferred small-molecule synthetic PLA2 inhibitors for use in the invention are selected from cytosolic PLA2 (cPLA2) inhibitors, calcium-independent PLA2 (iPLA2) inhibitors, secreted PLA2 (sPLA2) inhibitors and lipoprotein-associated PLA2 (LpPLA2) inhibitors, and mixtures of two or more thereof.

Preferred cPLA2 inhibitors for use in the invention include, but are not limited to, Giripladib, PF-5212372/ZPL-5212372, AVX001 , GK470, ASB14780, Pyrrophenone, RSC-3388, AACOCF3, and GK452, Quercetin, Honokiol, and mixtures of two or more thereof.

Preferred iPLA2 inhibitors for use in the invention include, but are not limited to GK187, FKGK11 , FKGK18, BEL, and mixtures of two or more thereof.

Preferred sPLA2 inhibitors for use in the invention include, but are not limited to, Varespladib, Varespladib methyl, AZD2716, GK241 , Celastrol, and mixtures of two or more thereof.

Preferred LpPLA2 inhibitors for use in the invention include, but are not limited to, Darabladib, Rilapladib, GSK2647544, SB-435495, and mixtures of two or more thereof. Preferred corticosteroids for use in the invention include glucocorticoids and mineralocorticoids as well as mixtures thereof.

Preferred glucocorticoids for use in the invention include, but are not limited to, beclometasone, betamethasone, cortison, deoxycorticosterone acetate, dexamethasone, fludrocortisone acetate, methylprednisolone, prednisone, prednisolone, triamcinolone as well as mixtures of two or more thereof, and most preferably is dexamethasone.

A preferred mineralocorticoid for use in the invention is aldosterone.

Preferred antibiotics for use in the invention include, but are not limited to, aminoglycosides, carbapenems, cephalosporins, fluoroquinolones, glycopeptides, lipoglycopeptides, ketolides, macrolides, monobactams, oxazolidinones, penicillins, polypeptide antibiotics, rifamycins, sulfonamides, streptogramins, tetracyclines, and mixtures of two or more thereof.

Preferred polypeptide antibobiotics include gramicidins. Preferred gramicidins include gramicidin D wich is a mix of ionophoric antibiotics, gramicidin A, B and C, which typically make up about 80%, about 5%, and about 15% of gramicidin D, respectively. Each of gramicidin A, B and C, respectively, exists in 2 isoforms. Typically, gramicidin D comprises or consists of six different types of gramicidin molecules, namely gramicidin A1 , A2, B1 , B2, C1 and 02. Gramicidin D, including gramicidine A1 , A2, B1, B2, C1 and C2, can be extracted from Brevibacillus brevis soil bacteria. Gramicidines contained in gramicidin D are linear peptides with having amino acids. Further gramicidins for use in the inventuin include the cyclic peptides gramicidin S, gramicidine J1 and gramicidin J2.

Specifically preferred antibiotics for use in the invention include, but are not limited to, vancomycin, telithromycin, erythromycin, aztreonamm, linezolid, tedizolid, quinupristin, dalfopristin, azithromycin, gramicidin D, gramicidin S and mixtures of two or more thereof, with azithromycin being particularly preferred.

Preferred PPAR agonists for use in the invention are typically selected from PPAR-alpha agonists, PPAR-gamma agonists, and PPAR-delta agonists, whereby specific PPAR agonists may have dual specificity such as being PPAR-alpha agonists and PPAR-gamma agonists, or being PPAR-gamma agonists, and PPAR-delta agonists, or being PPAR-alpha agonists, PPAR-delta agonists, and mixtures of two or more thereof. Preferred dual action PPAR agonists for use in the invention include, but are not limited to, aleglitazar, elafibranor, lobeglitazone muraglitazar, naveglitazar, saroglitazar, tesaglitazar, and mixtures of two or more thereof.

Other PPAR agonists have single or a predominantly specificity for a particular PPAR, for example the following preferred compounds:

Preferred PPAR-alpha agonists for use in the invention are fibrates, and preferred fibrates for use in the invention include, but are not limited to clofibrate, gemfibrozil, ciprofibrate, bezafibrate, fenofibrate, and mixtures of two or more thereof, with fenofibrate being a particularly preferred fibrate for use in the present invention.

Preferred PPAR-gamma agonists are typically selected from thiazolidinediones and AMG- 131 and mixtures thereof.

Preferred thiazolidinediones for use in the invention include, but are not limited to, Rosiglitazone and Pioglitazone and mixtures thereof.

Preferred PPAR-delta agonists include, but are not limited to, 15(S)-HETE, 15(R)-HETE, and 15-HpETE, GW0742, Telmisarta, and mixtures of two or more thereof.

Preferred protease inhibitors are typically selected from TMPRSS2 protease inhibitors and furin (PCSK3) protease inhibitors, and mixtures thereof.

Preferred TMPRSS2 protease inhibitors for use in the invention include, but are not limited to, bromhexine, nafamostat mesylate camostat mesylate, and mixtures of two or more thereof.

Other preferred protease inhibitors for use in the present invention include, but are not limited to, Amprenavir, Atazanavir, Darunavir, Fosamprenavir, Indinavir, Lopinavir, Nelfinavir, Ritonavir, Saquinavir, Tipranavir, Asunaprevir, Boceprevir, Grazoprevir, Glecaprevir, Paritaprevir, Simeprevir, Telaprevir, and mixtures of two or more thereof.

Preferred ACE2 receptor inhibitors/antagonists are typically selected from peptide ACE2 receptor inhibitors/antagonists, antibody ACE2 receptor inhibitors/antagonists, and small molecule ACE2 receptor inhibitors/antagonists as well as mixtures of two or more thereof. Preferred cytokine inhibitor or cytokine release inhibitors for use in the invention include, but are not limited to, interleukin receptor antagonists, bruton tyrosine kinase (BTK) inhibitors, a7Ach receptor agonists, prostaglandins inhibitors, cyclooxygenase inhibitors, plateletactivating factor inhibitors, tumour necrosis factor (TNF) inhibitors, and mixtures of two or more thereof.

Preferred interleukin receptor antagonists for use in the invention are antagonists of an interleukin receptor selected from the group consisting of IL-1 receptor, IL-6 receptor and IL- 33 receptor.

Preferred cytokine inhibitors or cytokine release inhibitors include, but are not limited to, acalabrutinib, adalimumab, anakinra, infliximab, siltuximab, tocilizumab (an IL-6 receptor antagonist), lenzilumab, and mixtures of two or more thereof.

Preferred free fatty acid receptor (FFAR) agonists for use in the invention are agonists of FFARs, preferably selected from FFAR1, FFAR2, FFAR3, FFAR4, and GPR84, with agonists of FFAR1 being particularly preferred.

Preferred SGLT l/ll inhibitor/antagonists for use in the present invention include, but are not limited to, canagliflozin, cloperastine, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin etabonate, sergliflozin etabonate, sotagliflozin, tofogliflozin, trihexyphenidyl, and mixtures of two or more thereof.

Preferred kinase inhibitor/antagonists for use in the invention include, but are not limited to, ARRY-797, apilimod, bencentinib, berzosertib, bosutinib, dasatinib, dinaciclib, gilteritinib, imatinib, nilotinib, ponatinib, ralimetinib, silmitasertib, tomivosertib, vistusertib, and mixtures of two or more thereof.

In other preferred embodiments kinase inhibitors/antagonists for use in the invention are preferably selected from Bruton’s tyrosine kinase (BTK) inhibitors, such as preferably acalabrutinib, ibrutinib, and zanubrutinib, and Janus kinase (JAK) inhibitors, such as preferably baricitinib, ruxolitinib, tofacitinib, and mixtures of two or more thereof.

Preferred interferons (IFNs) for use in the invention include, but are not limited to, IFNA1, IFNA2, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNA10, IFNA13, IFNA14, IFNA16, IFNA17, IFNA21 , IFNAB1 , IFNW, IFNAE1 , IFNK, interferon-alfa, interferon alfa 2a, interferon alfa 2b, Pegylated interferon alfa 2a, Pegylated interferon alfa 2b, Human leukocyte interferon-alpha, Interferon beta 1a, Interferon beta 1b, Interferon gamma 1b, and mixtures of two or more thereof.

Preferred interleukins (ILs) for use in the invention include IL 1 , IL 2, IL 3, IL IL 4, IL 5, IL 6, IL 7, IL 8, IL 9, IL 10, IL 11, IL 12, IL 13, IL 14, IL 15, IL 16, IL 17, IL 18, IL 19, IL 20, IL 21 , IL 22, IL 23, IL 24, IL 25, IL 26, IL 27, IL 28, IL 29, IL 30, IL 31 , IL 32, IL 33, IL 34, IL 35, IL 36, and mixtures of two or more thereof.

Preferred lipid lowering/dislipidemia drugs for use in the invention include, but are not limited to, acipimox, ApoA-1 Milano, avasimibe, bempedoic acid, bile acid sequestrants, CETP inhibitors, colesevelam, ezetimibe, implitapide, lecithin, lomitapide, mipomersen, niacin, Omega-3 supplements, PCSK9 inhibitors, phytosterols, squalene synthase inhibitor, statins, succinobucol, torcetrapib, and mixtures of two or more thereof.

Preferred PCSK9 inhibitors for use in the invention are typically selected from PCSK9 inhibiting antibodies, such as preferably alirocumab, evolocumab, 1D05-lgG2, RG-7652, LY3015014 and mixtures of two or more thereof, and PCSK9 targeted iRNA agents, such as preferably inclisiran.

Preferred bile acid sequestrants for use in the invention include, but are not limited to, Cholestyramine, Colestipol and Colesevelam, and mixtures of two or more thereof.

Preferred statins for use in the invention include, but are not limited to, atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, and mixtures of two or more thereof.

Preferred antihypertensives for use in the invention include, but are not limited to, aliskiren, amlodipine, benazepril, losartan, olmesartan, perindopril, Diltiazem valsartan, and mixtures of two or more thereof.

Preferred Bromodomain inhibitors for use in the invention include, but are not limited to, ABBV-744, CPI-0610, RVX-208, dBET6, JQ1, MZ1 , and mixtures of two or more thereof.

Preferred anti-inflammatory drugs for use in the invention include, but are not limited to nonsteroidal anti-inflammatory drugs, antileukotrienes, immune selective anti-inflammatory derivatives, and mixtures of two or more thereof. The pharmaceutical composition of the invention is particularly useful for treatment and/or prevention of a coronavirus infection.

Further subject matter of the invention is a method for treatment and/or prevention of a coronavirus infection comprising the step of administering an effective amount of the pharmaceutical composition according to the invention to a subject in need thereof, preferably a human subject.

The therapeutic and preventive, respectively uses of the invention of the invention also include such uses and methods, respectively, for treatment of coronavirus infection wherein the use or method, respectively, is generally a combined therapy (including preventive therapy) employing 2 or more, such as 2, 3, 4, or 5, preferably 2 or 3, most preferred 2, of the therapeutics according to the categories a) to w), including preferred embodiments thereof as outlined above. That means, according to the invention, that the 2 or more therapeutics selected from the categories a) to w) may not only be applied in the form of a single pharmaceutical composition as defined herein, but may also be applied in separate form, preferably in separate pharmaceutical compositions, either simultaneously or sequentially.

Thus, the invention also provides uses of a combination of 2 or more therapeutics selected from the categories a) to w), including preferred embodiments thereof as outlined above, treatment and/or prevention of a coronavirus infection.

Furthermore, the present invention provides a method for treatment and/or prevention of a coronavirus infection comprising the step of administering effective amounts of 2 or more, preferably 2, 3, 4, or 5, of the therapeutics of above-defined categories a) to w), including preferred embodiments thereof as outlined above, to a subject in need thereof, preferably a human subject.

In preferred embodiments of the invention, the coronavirus infection is caused by a coronavirus causing respiratory disease, more preferred pneumonia. In preferred embodiments, the coronavirus that infects humans. Preferably, the coronavirus is selected from the group consisting of SARS-CoV, MERS-CoV, SARS-CoV-2 and mutants thereof. Treatment and/or prevention of infections by SARS-CoV-2, or a mutant virus related to SARS-CoV-2, are especially preferred embodiments of the invention.

Mutants of a virus as defined herein have at least 80 %, preferably at least 90 %, more preferably at least 95 %, even more preferred at least 96 %, still further preferred at least 97 %, still further preferred at least 98 %, most preferred at least 99 % amino acid sequence homology with the wild-type coronavirus, especially preferred with the wild type SARS-CoV- 2.

In practicing the uses and methods, respectively, the pharmaceutical composition of the invention, or the combination of therapeutics as defined herein are preferably administered systemically or topically to a subject.

With respect to “topical administration” it is to be understood that, according to the invention, this term is considered to be the route of administration, and shall include administrations occurring locally, but having a systemic pharmacological effect.

A preferred topical administration of the inventive composition or combination of therapeutics involves administration to the respiratory tract of subject, including administration to the upper respiratory tract such as nasal and/or pharyngeal and/or laryngeal administration and/or administration to the mouth, and/or lower respiratory tract such as administration to the trachea and/or primary bronchi and/or lungs of a subject, preferably as an aerosol formulation, more preferably as a spray formulation, or a dry powder formudation.

In preferred embodiments of the invention, the inventive composition or combination of therapeutics, more preferably in the form of an aerosol or dry powder formulation or formulations, respectively, is/are administrated to the upper respiratory tract, more preferably by nasal administration. Nasal administration, also synonymously referred to according to the invention as “intra-nasal” administration, generally includes administration to the nasal cavity, and preferably comprises administration into one or both, preferably both, nostrils.

Systemic administration of the pharmaceutical composition or combination of therapeutics, respectively, is preferably by oral administration or by intravenous injection or infusion to a subject.

Typically, the pharmaceutical composition according to the invention, as well as any pharmaceutical composition comprising a therapeutic according to a category of a) to w) as defined herein (in particular, for providing a combination therapy with separated therapeutics as outlined above) contain the active pharmaceutical compound(s) (APC) or agents (APA), respectively, (i.e. the therapeutic(s) according to above categories a) to w), in combination with at least one pharmaceutically acceptable carrier. For carrying out the methods for therapeutic and/or preventive interventions as defined herein involving LA, it is preferred that the linoleic acid or derivative or salt or mimetic thereof is present in a composition containing said LA or derivative or salt or mimetic thereof. One preferred example of such a composition comprises liver cod oil.

Since hydrophobic substances such as fatty acids and related molecules, in particular LA, salts, derivatives and mimetics thereof as disclosed herein show a low degree of water solubility (about 100 mg/l in the case of LA), it is preferred to include an entity into a composition for use in the methods of the invention that increases the solubility of LA (or a derivative, a salt, or a mimetic thereof), in particular in aqueous solutions.

Also in in this context, the inventive composition comprises at least one, optionally pharmaceutically acceptable, carrier for lipophilic substances.

According to the invention, carriers for lipophilic substances can be components having one or more binding sites for lipophilic substances, in particular LA or derivative or salt or mimetic thereof as defined herein. According to the invention a carrier for LA or derivative or salt or mimetic thereof as defined herein can also be a solubilizer for lipophilic substances such as LA or derivative or salt or mimetic thereof as defined herein and/or for the inhibitor.

Preferred suitable carriers for lipophilic substances include, but are not limited to, proteins, lipoproteins, synthetic nanoparticles, carbohydrate matrices etc., preferably proteins, lipoproteins, synthetic nanoparticles, carbohydrate matrices etc. having one or more binding sites for LA or derivative or salt or mimetic thereof as defined herein and/or for the inhibitor. Suitable carriers for use in the invention are disclosed, e.g. in Kalepou et al. (2013) Acta Pharmaceutica Sinica B 3 (6), 361-372.

Preferred solubilizers for lipophilic substances in the context of the invention are cyclodextrin, ethanol, propylene glycol and a polypropylene glycol, including mixtures of two or more us such solubilizers.

The solubilizer(s) is/are and their amounts, in particular their molecular ratio to the LA or derivative or salt or mimetic thereof as defined and described herein, more preferably a compound of formula (I), most preferred LA and/or oleic acid, are preferably selected such that they substantially prevent formation of lipid vesicles, which will regularly form in particular in aqueous compositions. Preferred solubilizers prevent hydrophobic interaction between individual active substances (i.e. LA or derivative or salt or mimetic thereof as defined and described herein, more preferably a compound of formula (I), most preferred LA and/or oleic acid) by complexing the lipid molecules in a form such that they are shielded from a polar environment, in particular in aqueous solutions.

An especially preferred solubilizer for use in the invention is cyclodextrin (CD). Preferably, the cyclodextrin is an a-cyclodextrin, a p-cyclodextrin, a y-cyclodextrin, a 5-cyclodextrin or a mixture of two or more thereof.

In other preferred embodiments, the cyclodextrin, preferably an a-cyclodextrin, a - cyclodextrin, a y-cyclodextrin, a 5-cyclodextrin or a mixture of two or more thereof, is a cyclodextrin derivative selected from O-methylated, acetylated, hydroxypropylated, hydroxyethylated, hydroxyisobutylated, glucosylated, maltosylated and sulfoalkylether cyclodextrin and mixtures of two or more thereof. Derivatives of cyclodextrins are disclosed, e.g. in US Patent No. 5,760,017 and WO 91/13100 A1 Most preferred, the cyclodextrin is a P-cyclodextrin and/or a derivative thereof, preferably hydroxypropyl-p-cyclodextrin, such as 2 hydroxypropyl-p-cyclodextrin and/or 3- hydroxypropyl-p-cyclodextrin and/or 2,3- dihydroxypropyl-p-cyclodextrin, dimethyl-p-cyclodextrin, trimethyl-p-cyclodextrin, randomly methylated p-cyclodextrin, hydroxyethyl-p-cyclodextrin, 2-hydroxyisobutyl-p-cyclodextrin, glucosyl-p-cyclodextrin and maltosyl--p-cyclodextrin. Highly preferred cyclodextrins for use in the present invention are sulfoalkylether-modified cyclodextrins, preferably mixtures of such sulfoalkylether cyclodextrins, more preferred sulfoalkylether p-cyclodextrins, most preferred sulfobutylether-ss-cyclodextrin. Preferred alkylated and sulfoalkylated cyclodextrins and mixtures of such alkylated and sulfoalkylether dextrins are described in WO 98/50077 A1, WO 00/41704 A1, WO 2007/050075 A1, WO 2009/013434 A2, WP 2009/018069 A2, WO 2013/13666 A1 , WO 2016/029179 A1 and WO 2021/101842 A1. Preferred sulfoalkylether cyclodextrins, in particular mixtures of such sulfalkylether cyclodextrins, for use in the invention are available under the trademark Captisol®.

Further preferred examples of entities are increasing the solubility of lipophilic substances are proteins that can bind fatty acids, in particular LA (or a derivative or a salt or a mimetic thereof). More preferred proteins of this type are fatty acid binding proteins (FABPs) so that said composition preferably comprises at least one FABP together with LA or a derivative or salt of mutant thereof. FABPs for use in the present invention include FABP1 , FABP2, FABP3, FABP4, FABP5, FABP6, FABP7, FABP8, FABP9, FABP10, FABP11 and FABP12. Other preferred solubility improvers are albumin proteins, such as bovine serum albumin (BSA) or human serum albumin (HSA). The composition can therefore comprise one or more of such serum albumin proteins, optionally in addition to at least one FABP.

Linoleic acid (LA), or salts or derivatives or mimetics thereof, as described herein, wherein LA, the derivative, salt of mimetic thereof is used in combination with one or more non-LA therapeutics as defined herein for treatment and/or prevention of coronavirus infections.

“Non-LA therapeutics” of present invention refers to therapeutics of categories (b) to w) as outlined above. Preferably, such non-LA therapeutics are small molecule drugs that preferentially impact lipidomic systems (e.g. dislipidemia drugs) and/or metabolomic systems (e.g. catabolic and anabolic drugs).

The present invention includes methods for prevention and/or treatment of a coronavirus infection comprising the step of administering an effective amount of LA or a salt or a derivative or mimetic thereof in combination with one or more non-LA therapeutics to a human or animal subject, preferably a human subject.

An “effective amount” of an active substance for use in the inventive therapeutic or preventive, respectively, uses and methods as disclosed herein, preferably LA or a salt or a derivate of mimetic thereof as defined herein, together in combination with one or more non- LA therapeutics as defined herein. An “effective amount” is an amount of the active substance(s) exerting an effect suitable for at least improving the condition, in particular of a coronavirus infection as disclosed herein, especially COVID-19, preferably substantially improving said condition, optimally curing said condition.

With respect to LA or a salt or a derivate of mimetic thereof as defined herein, most preferred LA, an effective amount is preferably in the range in a daily dose, which may be administered in one or more unit doses, of about 1 mg/kg body weight to about 1400 mg/kg body weight, more preferably about 5 mg/kg body weight to about 50 mg/kg body weight, wherein body weight means weight of the subject treated.

With respect to the one or more non-LA therapeutics according to categories b) to w) as defined herein to be used alone or in combination with LA or a salt or a derivate of mimetic thereof as defined herein, a preferred effective amount is, e.g., a daily dose, which may be administered in one or more unit doses, of about 0.1 mg/kg bodyweight to about 50 mg/kg bodyweight, more preferred of about 1 mg/kg bodyweight to about 10 mg/kg bodyweight, wherein body weight means weight of the subject treated. Therapeutics as defined herein are useful for the treatment and/or prevention of a coronavirus infection. The present invention is also directed to methods for prevention and/or treatment of a coronavirus infection comprising the step of administering an effective amount one or more non-LA therapeutics as defined herein to a subject, preferably a human subject, in need thereof. The present invention is also directed to the use of combinations of two or more non-LA therapeutics for the preparation of a medicament for the treatment and/or prevention of a coronavirus infection. Preferably, the coronavirus infection is an infection by a coronavirus causing a respiratory disease, in particular pneumonia, preferably in humans. More preferred, the coronavirus infection is an infection by SARS-CoV, MERS-CoV and/or SARS-CoV-2, with infections by SARS-CoV-2 are most preferred.

The LA or derivative or salt or mimetic thereof and/or the at least one non-LA therapeutics may be administered systemically or topically to a subject. Similarly, the administration of two or more non-LA therapeutics in the absence of LA or derivative or salt or mimetic thereof may be administered systemically or topically to a subject.

A preferred topical administration of the active substance(s) (i.e. LA or derivative or salt or mimetic thereof and/or one, two or more non-LA therapeutics as defined herein) involves administration to the lungs of a subject, preferably as an aerosol formulation of the active compound(s).

Systemic administration of the active substance(s) (i.e. LA or derivative or salt or mimetic thereof and/or one, two or more non-LA therapeutics as defined herein) is preferably carried out by administering the active substance(s) orally and/or by intra-venous infection to a subject.

Oral administration can by embodied by mixing the active substance(s) with a food.

Preferably, the LA or derivative or salt or mimetic thereof and/or one, two or more non-LA therapeutics as defined herein is/are administered in the form of a composition comprising the LA or derivative or salt or mimetic thereof and/or one, two or more non-LA therapeutics as defined herein with at least one, optionally pharmaceutically acceptable, carrier for lipophilic substances.

Preferred suitable carriers for lipophilic substances include, but are not limited to, proteins, lipoproteins, synthetic nanoparticles, carbohydrate matrices etc., preferably proteins, lipoproteins, synthetic nanoparticles, carbohydrate matrices etc. having one or more binding sites for linoleic acid or derivative or salt or mimetic thereof as defined herein and/or for the inhibitor. Suitable carriers for use in the invention are disclosed, e.g. in Kalepou et al. (2013) Acta Pharmaceutica Sinica B 3 (6), 361-372.

Preferred proteins of this type are, e.g., albumin proteins, preferably human serum albumin, and fatty acid binding proteins, preferably one or more selected from FABP1 , FABP2, FABP3, FABP4, FABP5, FABP6, FABP7, FABP8, FABP9, FABP10, FABP11 and FABP12.

In the therapeutic and/or preventive methods as well as uses as disclosed herein, it is particularly preferred when the LA or derivative or salt or mimetic thereof as defined herein and/or one, two or more non-LA therapeutics as defined herein as defined herein is mixed with the carrier ex vivo before administration to the subject.

In addition to the above components for use in preventive and/or therapeutic methods and uses as disclosed herein, compositions for use in the invention containing the above active components, preferably in admixture with a lipophilic carrier, may contain further ingredients typically present in dosage for oral or intravenous (IV) injection application for providing and/or improving various parameters. Typical additional ingredients for use in the present invention include excipients, other carriers, fillers, glidants, dispersants, plasticizers, wetting agents, anti-tacking agents, neutralization agents, colorants, pigments, opacifiers, flavours, taste improvement agents such as sweeteners, buffers, injection-aids, and the like. The person skilled in the art of formulating compositions for preventive and/or therapeutic uses and methods as disclosed herein is readily able to identify specific compounds and substances of the above and other types as well as their combinations and amounts to be used. Further guidance can be found in Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, in particular pages 1289-1329.

The present invention is further illustrated by the following non-limiting examples:

EXAMPLES

Example 1:

Quantitative determination of potential effectiveness of a given combination therapy for treating human coronavirus infection. Quantification of potential effectiveness of a given combination therapy for treating coronavirus infection can be carried out by an in vitro experiment which investigates the effect of one component of the therapy with and without the second or more additional components of the combination therapy in a cell culture experiment which determines inhibition of coronavirus replication. It is anticipated that if a combination therapy is potentially effective as a therapeutic intervention for coronavirus infection, the presence of only one component of the therapy in inhibiting coronavirus replication will be less effective than a combination of the first component with a second (or more) additional therapeutics of the potential combination therapy.

To determine the antiviral effects of drugs, or drug combinations, respectively, following the protocol of Muller et al (28), confluent cell monolayers of Huh-7, HeLa , BHK-21 , A549, and Vero or Caco2 cells are infected at a multiplicity of infection (MOI) of 3. This means 3 coronavirus particles per mammalian cell. After 2 h, the virus inoculum is removed, cells rinsed with PBS, and fresh medium containing the concentrations of drugs or DMSO (solvent control) is added. At 12 h post infection the cell culture supernatant is collected, and viral particle titer is determined by RT-PCR (29,30) or by Plaque Assay (28). For an example of the result of such an experiment please see below Table 1.

Table 1 : Theoretical reduction in virus titer.

A person of ordinary technical skill could use this general strategy to test for the potential effectiveness of a given combination therapy in therapeutic intervention of coronavirus infection.

References Cited

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4 Yan, B. et al. Characterization of the Lipidomic Profile of Human Coronavirus-Infected Cells: Implications for Lipid Metabolism Remodeling upon Coronavirus Replication. Viruses 11, doi:10.3390/v11010073 (2019).

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7 Grasselli, G. et al. Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy. JAMA, doi:10.1001/jama.2020.5394 (2020). 8 Cummings, M. J. etal. Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study. Lancet, doi : 10.1016/S0140-6736(20)31189-2 (2020) .

9 Hoffmann, M. et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 181 , 271-280 e278, doi:10.1016/j. cell.2020.02.052 (2020).

10 Matsuyama, S. et al. Enhanced isolation of SARS-CoV-2 by TMPRSS2-expressing cells. Proc Natl Acad ScIL/ SA I VT, 7001-7003, doi: 10.1073/pnas.2002589117 (2020).

11 Hoffmann, M., Kleine-Weber, H. & Pohlmann, S. A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells. Mol Cell 78, 779-784 e775, doi:10.1016/j.molcel.2020.04.022 (2020).

12 Du, L. et al. The spike protein of SARS-CoV--a target for vaccine and therapeutic development. Nat Rev Microbiol 7, 226-236, doi:10.1038/nrmicro2090 (2009).

13 Letko, M., Marzi, A. & Munster, V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol 5, 562- 569, doi:10.1038/s41564-020-0688-y (2020).

14 Walls, A. C. et al. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell 181 , 281-292 e286, doi:10.1016/j.cell.2020.02.058 (2020).

15 Kindler, E. & Thiel, V. To sense or not to sense viral RNA--essentials of coronavirus innate immune evasion. Curr Opin Microbiol 20, 69-75, doi:10.1016/j.mib.2014.05.005 (2014).

16 Kikkert, M. Innate Immune Evasion by Human Respiratory RNA Viruses. J Innate Immun 12, 4-20, doi: 10.1159/000503030 (2020).

17 Zang, R. et al. TMPRSS2 and TMPRSS4 promote SARS-CoV-2 infection of human small intestinal enterocytes. Sci Immunol 5, doi: 10.1126/sciimmunol.abc3582 (2020).

18 Qin, C. et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis, doi:10.1093/cid/ciaa248 (2020).

19 Ziegler, C. G. K. et al. SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues. Cell 181, 1016-1035 e1019, doi:10.1016/j.cell.2020.04.035 (2020).

20 Toelzer, C. et al. Unexpected free fatty acid binding pocket in the cryo-EM structure of SARS-CoV-2 spike protein, doi: https://doi.org/10.1101/2020.06.18.158584

21 Shen, B. etal. Proteomic and Metabolomic Characterization of COVID-19 Patient Sera. Cell, doi:10.1016/j. cell.2020.05.032 (2020).

22 Goodwin, C. M., Xu, S. & Munger, J. Stealing the Keys to the Kitchen: Viral Manipulation of the Host Cell Metabolic Network. Trends Microbiol 23, 789-798, doi:10.1016/j.tim.2015.08.007 (2015). Schoggins, J. W. & Randall, G. Lipids in innate antiviral defense. Cell Host Microbe 14, 379-385, doi:10.1016/j.chom.2013.09.010 (2013). Nagamine, T., Inaba, T. & Sako, Y. A nuclear envelop-associated baculovirus protein promotes intranuclear lipid accumulation during infection. Virology 532, 108-117, doi:10.1016/j.viroL2019.04.006 (2019). Ehrlich, A. et al. The SARS-CoV-2 Transcriptional Metabolic Signature in Lung Epithelium. http://dx.doi.Org/10.2139/ssrn.3650499 Zaman, M. M. et al. Linoleic acid supplementation results in increased arachidonic acid and eicosanoid production in CF airway cells and in cftr-/- transgenic mice. Am J Physiol Lung Cell Mol Physiol 299, L599-606, doi:10.1152/ajplung.00346.2009 (2010). Richieri GV, Ogata RT, Kleinfeld AM. The measurement of free fatty acid concentration with the fluorescent probe ADI FAB: a practical guide for the use of the ADI FAB probe. Mol Cell Biochem. 1999; 192(1 -2):87-94. Muller, C. et al. Inhibition of Cytosolic Phospholipase A2a Impairs an Early Step of Coronavirus Replication in Cell Culture. Journal of Virology 92, 4 (2018): e01463-17. Jared Bullard, J. et al. Predicting infectious SARS-CoV-2 from diagnostic samples. Clinical Infectious Diseases, , ciaa638, https://d0i.0rg/l 0.1093/cid/ciaa638 Han MS, Byun JH, Cho Y, Rim JH. RT-PCR for SARS-CoV-2: quantitative versus qualitative [published online ahead of print, 2020 May 20], Lancet Infect Dis. 2020;S1473-3099(20)30424-2. doi:10.1016/S1473-3099(20)30424-2

Claims

1 . A pharmaceutical composition comprising 2 or more of the therapeutics selected from the group consisting of the following categories a) to w) a) linoleic acid, a derivative, salt or mimetic thereof; b) a broad-spectrum antiviral agent (BSAA); c) a nucleoside analogue; d) a Phospholipase A2 (PLA2) inhibitor; e) a corticosteroid; f) an antibiotic; g) a peroxisome proliferator-activated receptor (PPAR) agonist; h) a protease inhibitor; i) an angiotensin-converting enzyme 2 (ACE2) receptor inhibitor/antagonist; j) a cytokine inhibitor or cytokine release inhibitor; k) a free fatty acid receptor (FFAR) agonist; l) a SGLT l/ll inhibitor/antagonist; m) a kinase inhibitor; n) an interferon; o) an interleukin; p) a lipid lowering/dislipidemia drug; q) an antihypertensive; r) a Bromodomain inhibitor; s) an anti-inflammatory; t) a pulmonary fibrosis (PF) drug, preferably selected from the group consisting of Nintedanib, and Pirfenidone; u) an anticancer drug, preferably selected from the group consisting of Selinexor, zotatifin, Plitidepsin and Pevonedistat, v) an antihyperglycemic, preferably ternatin-4, and w) an antihistamine, preferably selected from the group consisting of haloperidol, melperone, clemastine and/or cloperastine.

2. The composition of claim 1 wherein the derivative or mimetic of linoleic acid of claim 1a) is characterised by the following general formula (I):

33 wherein

Q is selected from O, S and NH;

R1 is selected from OH, NH2, and SH; and

R2 is a straight hydrocarbyl group having from 13 to 21 C atoms, preferably 17 C atoms, optionally linked or bound to a detectable label. The composition of claim 2 wherein R2 has at least one unsaturated C-C bond. The composition of claim 3 wherein R2 has two unsaturated C-C bonds. The composition of claim 4 wherein the two unsaturated C-C bonds of claim 4 are between C-8 and C-9 and between C-11 and C-12 of the hydrocarbyl group when counted from the carbon bound to the C=Q group in formula (I). The composition of claim 2 wherein the derivative or mimetic is selected from the group consisting of oleic acid, arachidonic acid, elaidic acid, eicosapentaenoic acid, stearic acid, gamma-linoleic acid, calendic acid, arachidic acid, dihomo-gamma- linoleic acid, docosadienoic acid, adrenic acid, palmitic acid and behenic acid. The composition of claim 6 wherein the derivative or mimetic is oleic acid. The composition according to any one of the preceding claims wherein the Broadspectrum antiviral agent (BSAA) is selected from the group consisting of Nitazoxanide, Favipiravir, Mycophenolic acid, Remdesivir, Cidofovir, Chloroquine, Niclosamide, Amodiaquine, Brincidofovir, El PA (amiloride), Emetine, BCX4430 (Galidesivir), Gemcitabine, Rapamycin (Sirolimus), ABT-263, Berberine, Cyclosporine, Brequinar, Obatoclax, Luteolin, Ribavirin, Tilorone (Amixin), Glycyrrhizin, Eflornithine, Sorafenib, Suramin, Monensin, Arbidol (Umifenovir), Sunitinib, Labyrinthopeptin A2, Silvestrol, Emodin, Amiodarone, Raloxifene, Azithromycin, Ivermectin, Labyrinthopeptin A1 , Mitoxantrone, Ganciclovir, Letermovir, Artesunate, Dasatinib, Chlorpromazine, Hydroxychloroquine, Foscarnet, Simvastatin, Bortezomib, Camptothecin, Homoharringtonine, Itraconazole, Azacitidine, Leflunomide, Nelfinavir, Valacyclovir, 4-HPR (Fenretinide), Aprotinin, Topotecan, Oritavancin, Tamoxifen, Novobiocin, Pentosan polysulfate, Ezetimibe, Lopinavir, Filociclovir, Isolanid (lanatoside C), Sofosbuvir, Manidipine, Anisomycin, Lovastatin, Metformin, Minocycline, Benztropine, Dalbavancin, Teicoplanin, N-MCT, Roscovitine (Seliciclib), Caffeine, Genistin, Regorafenib, Alisporivir, Cepharanthine, Mefloquine, Erlotinib, Gefitinib, Hexachlorophene, Imatinib, Lobucavir, Verapamil, Apoptozole, Fluoxetine, Fluvastatin, Posaconazole, Quinacrine, Nafamostat, Teriflunomide, Aciclovir, Acetylsalicylic acid, Camostat, Memantine, Tenofovir, Dibucaine, Pirlindole, Formoterol, Pleconaril, Indomethacin, Ritonavir, Flavopiridol, Bithionol, Doxycycline, Salinomycin, Saracatinib, Bepridil, Quinine, Clomipramine, Diphyllin, Telavancin, Toremifene, Promethazine, Kasugamycin, Trametinib, Zanamivir, CYT107, Lamivudine, Thymalfasin, Atovaquone, Irbesartan, PS3061 , Alpha-lipoic acid and mixtures of 2 or more thereof. The composition according to any one of the preceding claims wherein the nucleoside analogue is selected from the group consisting of deoxyadenosine analogues, adenosine analogues, deoxycytidine analogues, guanosine analogues, deoxyguanosine analogues, thymidine analogues, deoxythymidine analogues, deoxyuridine analogues and mixtures of 2 or more thereof. The composition according to any one of claims 1 to 8 wherein the nucleoside analogue is selected from the group consisting comprising abacavir, aciclovir, cytarabine, didanosine, emtricitabine, entecavir, favipiravir, galidesivir, gemcitabine, idoxuridine, lamivudine, remdesivir, ribavirin, stavudine, taribavirin, telbivudine, trifluridine, vidarabine, zalcitabine, zidovudine and mixtures of 2 or more thereof. The composition according to any one of the preceding claims wherein the smallmolecule synthetic PLA2 inhibitor is selected from the group consisting of cytosolic PLA2 (cPLA2) inhibitors, calcium-independent PLA2 (iPLA2) inhibitors, secreted PLA2 (sPLA2) inhibitors, lipoprotein-associated PLA2 (LpPLA2) inhibitors and mixtures of 2 or more thereof. The composition of claim 12 wherein the cPLA2 inhibitor is selected from the group consisting of Giripladib, PF-5212372/ZPL-5212372, AVX001, GK470, ASB14780, Pyrrophenone, RSC-3388, AACOCF3, and GK452, Quercetin, Honokiol and mixtures of 2 or more thereof. The composition of claim 11 wherein the iPLA2 inhibitor is selected from the group consisting of GK187, FKGK11 , FKGK18, BEL and mixtures of 2 or more thereof. The composition of claim 11 wherein the sPLA2 inhibitor is selected from the group consisting of Varespladib, Varespladib methyl, AZD2716, GK241 , Celastrol and mixtures of 2 or more thereof. The composition of claim 11 wherein the LpPLA2 inhibitor is selected from the group consisting of Darabladib, Rilapladib, GSK2647544, SB-435495 and mixtures of 2 or more thereof. The composition according to any one of the preceding claims wherein the corticosteroid is a glucocorticoid. The composition of claim 16 wherein the glucocorticoid is selected from the group consisting of beclometasone, betamethasone, cortison, deoxycorticosterone acetate, dexamethasone, fludrocortisone acetate, methylprednisolone, prednisone, prednisolone, triamcinolone, and mixtures of 2 or more thereof, and most preferably is dexamethasone. The composition according to any one of the preceding claims wherein the corticosteroid is a mineralocorticoid. The composition of claim 18 wherein the mineralocorticoid is aldosterone. The composition according to any one of the preceding claims wherein the antibiotic is selected from the group consisting of aminoglycosides, carbapenems, cephalosporins, fluoroquinolones, glycopeptides, lipoglycopeptides, ketolides, macrolides, monobactams, oxazolidinones, penicillins, polypeptide antibiotics, rifamycins, sulfonamides, streptogramins, tetracyclines and mixtures of 2 or more thereof. The composition of claim 20 wherein the antibiotic is selected from the group consisting of vancomycin, telithromycin, erythromycin, aztreonamm, linezolid, tedizolid, quinupristin, dalfopristin, azithromycin, gramicidin D, gramicidin S and mixtures of 2 or more thereof.

22. The composition of claim 21 wherein the antibiotic is azithromycin.

23. The composition according to any one of the preceding claims wherein the PPAR agonist g) is selected from the group comprising PPAR-alpha agonists, PPAR- gamma agonists, PPAR-delta agonists and mixtures of 2 or more thereof.

24. The composition of claim 23 wherein the PPAR agonist is selected from the group consisting of aleglitazar, elafibranor, lobeglitazone muraglitazar, naveglitazar, saroglitazar, tesaglitazar and mixtures of 2 or more thereof.

25. The composition of claim 23 wherein the PPAR-alpha agonist is a fibrate.

26. The composition of claim 25 wherein the fibrate is selected from the group consisting of clofibrate, gemfibrozil, ciprofibrate, bezafibrate, fenofibrate and mixtures of 2 or more thereof.

27. The composition of claim 25 wherein the fibrate is fenofibrate.

28. The composition of claim 23 wherein the PPAR-gamma agonist is selected from the group consisting of thiazolidinediones and AMG-131 and mixtures thereof.

29. The composition of claim 28 wherein the thiazolidinedione is selected from the group consisting of Rosiglitazone, Pioglitazone and mixtures of 2 or more thereof.

30. The composition of claim 23 wherein the PPAR-delta agonist is selected from 15(S)- HETE, 15(R)-HETE, 15-HpETE, GW0742, Telmisartan and mixtures of 2 or more thereof.

31 . The composition according to any one of the preceding claims wherein the protease inhibitor is selected from the group consisting of TMPRSS2 protease inhibitors and furin (PCSK3) protease inhibitors and mixtures thereof.

32. The composition of claim 31 wherein the TMPRSS2 protease inhibitor is selected from the group consisting of bromhexine, nafamostat mesylate, camostat mesylate and mixtures of 2 or more thereof.

37 The composition of claim 31 wherein the protease inhibitor is selected from the group consisting of Amprenavir, Atazanavir, Darunavir, Fosamprenavir, Indinavir, Lopinavir, Nelfinavir, Ritonavir, Saquinavir, Tipranavir, Asunaprevir, Boceprevir, Grazoprevir, Glecaprevir, Paritaprevir, Simeprevir, Telaprevir and mixtures of 2 or more thereof. The composition according to any one of the preceding clams wherein the ACE2 receptor inhibitor/antagonist is selected from the group consisting of peptide ACE2 receptor inhibitors/antagonists, antibody ACE2 receptor inhibitors/antagonists, small molecule ACE2 receptor inhibitors/antagonists and mixtures of 2 or more thereof. The composition according to any one of the preceding claims wherein the cytokine inhibitor or cytokine release inhibitor is selected from the group consisting of interleukin receptor antagonists, bruton tyrosine kinase (BTK) inhibitors, a7Ach receptor agonists, prostaglandins inhibitors, cyclooxygenase inhibitors, plateletactivating factor inhibitors, tumour necrosis factor (TNF) inhibitors and mixtures of 2 or more thereof. The composition of claim 35 wherein the interleukin receptor antagonist is an antagonist of an interleukin receptor selected from the group consisting of IL-1 receptor, IL-6 receptor and IL-33 receptor. The composition according to any one of the preceding claims wherein the cytokine inhibitor or cytokine release inhibitor is selected from the group comprising acalabrutinib, adalimumab, anakinra, infliximab, siltuximab, tocilizumab, lenzilumab, and mixtures of 2 or more thereof. The composition according to any one of the preceding claims wherein the free fatty acid receptor (FFAR) is selected from the group consisting of FFAR1, FFAR2, FFAR3, FFAR4, GPR84 and mixtures of 2 or more thereof, and is preferably FFAR1. The composition according to any one of the preceding claims wherein the SGLT l/ll inhibitor/antagonist is selected from the group consisting of canagliflozin, cloperastine, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, remogliflozin etabonate, sergliflozin etabonate, sotagliflozin, tofogliflozin, trihexyphenidyl and mixtures of 2 or more thereof.

38 The composition according to any one of the preceding claims wherein the kinase inhibitor/antagonist is selected from the group consisting of ARRY-797, apilimod, bencentinib, berzosertib, bosutinib, dasatinib, dinaciclib, gilteritinib, imatinib, nilotinib, ponatinib, ralimetinib, silmitasertib, tomivosertib, vistusertib and mixtures of 2 or more thereof. The composition according to any one of claims 1 to 39 wherein the kinase inhibitor/antagonist is selected from the group consisting of Bruton’s tyrosine kinase (BTK) inhibitors, preferably acalabrutinib, ibrutinib, and zanubrutinib or Janus kinase (JAK) inhibitors and mixtures of 2 or more thereof, and is preferably selected from the group consisting of baricitinib, ruxolitinib, tofacitinib and mixtures of 2 or more thereof. The composition according to any one of the preceding claims wherein the interferon (IFN) is selected from the group consisting of IFNA1, IFNA2, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNA10, IFNA13, IFNA14, IFNA16, IFNA17, IFNA21 , IFNAB1 , IFNW, IFNAE1 , IFNK, interferon-alfa, interferon alfa 2a, interferon alfa 2b, Pegylated interferon alfa 2a, Pegylated interferon alfa 2b, Human leukocyte interferon-alpha, Interferon beta 1a, Interferon beta 1b, Interferon gamma 1b, and mixtures of 2 or more thereof. The composition according to any one of the preceding claims wherein the interleukin (I L) is selected from the group consisting of I L 1 , IL 2, IL 3, IL IL 4, IL 5, IL 6, IL 7, IL 8, IL 9, IL 10, IL 11, IL 12, IL 13, IL 14, IL 15, IL 16, IL 17, IL 18, IL 19, IL 20, IL 21, IL 22, IL 23, IL 24, IL 25, IL 26, IL 27, IL 28, IL 29, IL 30, IL 31, IL 32, IL 33, IL 34, IL 35, IL 36, and mixtures of 2 or more thereof. The composition according to any one of the preceding claims wherein the lipid lowering/dislipidemia drug of is selected from the group consisting of acipimox, ApoA- 1 Milano, avasimibe, bempedoic acid, bile acid sequestrants, CETP inhibitors, colesevelam, ezetimibe, implitapide, lecithin, lomitapide, mipomersen, niacin, Omega- 3 supplements, PCSK9 inhibitors, phytosterols, squalene synthase inhibitor, statins, succinobucol, torcetrapib and mixtures of 2 or more thereof. The composition of claim 44 wherein the PCSK9 inhibitor is selected from the group consisting of PCSK9 inhibiting antibodies and PCSK9 targeted iRNA agents, and mixtures thereof.

39

46. The composition of claim 45 wherein the PCSK9 inhibiting antibody is selected from the group consisting of alirocumab, evolocumab, 1D05-lgG2, RG-7652, LY3015014 and mixtures of 2 or more thereof.

47. The composition of claim 45 wherein the PCSK9 targeted iRNA agent is inclisiran.

48. The composition of claim 46 wherein the bile acid sequestrant is selected from the group consisting of Cholestyramine, Colestipol, Colesevelam and mixtures of 2 or more thereof.

49. The composition of claim 4 wherein the statin is selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin and mixtures of 2 or more thereof.

50. The composition according to any one of the preceding claims wherein the antihypertensive is selected from the group consisting of aliskiren, amlodipine, benazepril, losartan, olmesartan, perindopril, Diltiazem, valsartan and mixtures of 2 or more thereof.

51 . The composition according to any one of the preceding claims wherein the Bromodomain inhibitor is selected from the group consisting of ABBV-744, CPI-0610, RVX-208, dBET6, JQ1, MZ1 and mixtures of 2 or more thereof.

52. The composition according to any one of the preceding claims wherein the antiinflammatory is selected from the group consisting of nonsteroidal anti-inflammatory drugs, antileukotrienes, immune selective anti-inflammatory derivatives and mixtures of 2 or more thereof.

53. The composition according to any one of the preceding claims for use in the treatment and/or prevention of a coronavirus infection.

54. A combination of two or more of the therapeutics selected from the group consisting of the categories a) to w) as defined in any one of claim 1 to 52 for use in the treatment and/or prevention of a coronavirus infection wherein the therapeutics are administered simultaneously or sequentially to a subject.

40

55. The composition or combination of therapeutics for use of claim 53 or 54 wherein the composition or combination of therapeutics is administered systemically or topically to a subject.

56. The composition or combination of therapeutics for use of claim 54 or 55 wherein the composition or combination of therapeutics is administered to the respiratory tract of a subject.

57. The composition or combination of therapeutics for use of claim 56 wherein the administration of the composition or combination of therapeutics is selected from the group consisting of nasal administration and/or pharyngeal administration and/or intra4aryngeal administration and/or administration to the mouth and/or administration to the lower respiratory tract.

58. The composition or combination of therapeutics for use of claim 57wherein the administration to the lower respiratory tract is selected from the group consisting of administration to the trachea and/or administration to the primary bronchi and/or or administration to the lungs of a subject.

59. The composition or combination of therapeutics for use according to any one of claims 56 to 58 wherein the composition or combination of therapeutics is administered as an aerosol formulation or a dry powder formulation.

60. The composition or combination of therapeutics for use of claim 55 wherein the composition or combination of therapeutics is administered orally to a subject.

61 . The composition or combination of therapeutics for use of claim 55 wherein the composition or combination of therapeutics is administered by intra-venous injection to a subject.

62. The composition or combination of therapeutics for use according to any of claims 53 to 61 wherein the composition or combination of therapeutics is administered in combination with at least one, optionally pharmaceutically acceptable, carrier for lipophilic substances.

63. The composition or combination of therapeutics for use of claim 62 wherein the, optionally pharmaceutically acceptable, carrier is selected from the group consisting

41 of proteins, lipoproteins, synthetic nanoparticles, and carbohydrate matrices, wherein said carrier has one or more binding sites for the linoleic acid or derivative or salt or mimetic thereof.

64. The composition or combination of therapeutics for use of claim 60 wherein the protein is selected from the group consisting of albumin proteins and fatty acid binding proteins.

65. The composition or combination of therapeutics for use of claim 61 wherein the albumin protein is human serum albumin.

66. The composition or combination of therapeutics for use of claim 63 wherein the carrier is a fatty acid solubilizer.

67. The composition or combination of therapeutics for use of claim 66 wherein the fatty acid solubilizer is selected from the group consisting of cyclodextrin, ethanol, propylene glycol and a polypropylene glycol, and mixtures of two or more thereof.

68. The composition or combination of therapeutics for use of claim 67 wherein the cyclodextrin is a p-cyclodextrin.

69. The composition or combination of therapeutics for use of claim 68 wherein the cyclodextrin is selected from the group consisting of O-methylated, acetylated, hydroxypropylated, hydroxyethylated, hydroxyisobutylated, glucosylated, maltosylated and sulfoalkylether-p-cyclodextrin and mixtures of two or more thereof.

70. The composition or combination of therapeutics for use according to any one of claims 62 to 69 wherein the composition or combination of therapeutics is mixed with the carrier ex vivo before administration to the subject.

71 . The composition or combination of therapeutics for use of claim 70 wherein orally administering the composition or combination of therapeutics comprises mixing it with a food.

72. The composition or combination of therapeutics for use according to any one of claims 53 to 71 wherein the coronavirus causes a respiratory disease, preferably in humans.

42 The composition or combination of therapeutics for use of claim 72 wherein the coronavirus causes pneumonia. The composition or combination of therapeutics for use of claim 72 or 73 wherein the coronavirus of claim is selected from the group consisting of SARS-CoV, MERS-CoV,

SARS-CoV-2, and mutants thereof. The composition or combination of therapeutics for use of claim 74 wherein the coronavirus is SARS-CoV-2, or a mutant virus related to SARS-CoV-2. The composition or combination of therapeutics for use of claim 74 or 75 wherein the mutant virus has at least 80 %, preferably at least 90 %, more preferably at least 95 %, even more preferred at least 96 %, still further preferred at least 97 %, still further preferred at least 98 %, most preferred at least 99 % amino acid sequence homology with the wild-type virus, preferably with the wild-type SARS-CoV-2.

43