WO2021180742A1

WO2021180742A1 - Methyl-cyclodextrin for use in treating enveloped virus infections such as cov-2

Info

Publication number: WO2021180742A1
Application number: PCT/EP2021/055951
Authority: WO
Inventors: Patrice Garnier; Marc Salome; Antoine Danchin
Original assignee: Virtexx
Priority date: 2020-03-09
Filing date: 2021-03-09
Publication date: 2021-09-16

Abstract

The present invention relates to composition comprising at least one methyl- cyclodextrin for use in a method of prevention or treatment of an infection by an enveloped virus, in particular of the Coronaviridae family, in an individual.

Description

METHYL-CYCLODEXTRIN FOR USE IN TREATING ENVELOPED VIRUS INFECTIONS SUCH AS COV-2

Domain of the invention

The present invention relates to compounds and methods for treating infections by enveloped viruses, in particular belonging †o the Coronaviridae family, more particularly by the virus SARS-CoV-2.

Technical Background

In December 2019 an outbreak of pneumonia cases of unknown origin in occurred in Wuhan in China and spread quickly nationwide. On January 7, 2020, the causative pathogen was identified as a novel coronavirus, which was named 2019- nCoV and later SARS-CoV-2.

The new virus is closely related †o both SARS-CoV (82% nucleotide identify) and MERS- CoV (50% nucleotide identify), ye† distinct from them.

Early mortality rates suggested †ha† COVID-19, the name for the disease caused by SARS-CoV-2, may be less severe than SARS and MERS. However, illness onset among rapidly increasing numbers of people suggests †ha† SARS-CoV-2 is more contagious than both SARS-CoV and MERS-CoV. As of March 5, 2021, 1 15 618088 cases of COVID- 19 (in accordance with the applied case definitions and testing strategies in the affected countries) have been reported, including 2569422 deaths.

A great deal of effort has been made †o find effective drugs against the virus.

Among the various compounds tested, chloroquine phosphate, a drug previously used for the treatment of malaria, has demonstrated promising efficacy and acceptable safety in treating COVID-19-associa†ed pneumonia in multi-center clinical trials conducted in China (Goa e† al. (2020) BioScience Trends, DOI: 10.5582/bs†.2020.01047). However, the clinical efficacy chloroquine phosphate has no† been completely established. Besides, chloroquine phosphate is responsible for various side effects, including allergies.

Besides, remdesivir, a drug previously developed for the treatment of Ebola virus infections, has been reported †o show promising efficacy and acceptable safety in treating COVID-19 in Beigel et al. (2020) N Engl J Med 383:1813-26. As such, results indicate remdesivir was superior †o placebo in shortening the time †o recovery in adults who were hospitalized with COVID-19 and had evidence of lower respiratory tract infection. However, the efficacy of remdesivir is no† established as Wang et al. (2020) Lance† doi.org/10.1016/S0140-6736(20)31022-9 report that in their trial remdesivir use was no† associated with a difference in time †o clinical improvement.

Accordingly, there is still a need for alternative compounds for treating infections by SARS-CoV-2.

Summary of the invention The present invention arises from the unexpected finding, by the inventors, †ha† a me†hyl-p-cyclodex†rin could be effective in an in vitro model of infection by enveloped virus SARS-CoV-2. Without wishing †o be bound †o a particular theory, the inventors believe me†hyl-cyclodex†rins as defined herein could impair the functioning of viral lipid envelopes.

Accordingly, the present invention relates †o a composition comprising a† leas† one me†hyl-cyclodex†rin for use in a method of prevention or treatment of an infection by an enveloped virus, in particular of the Coronaviridae family, in an individual.

The present invention also relates †o a composition for use according as defined above, in combination with a† leas† one other compound suitable for the prevention or treatment of an infection by a enveloped virus, in particular of the Coronaviridae family, more particularly by SARS-CoV-2.

The present invention also relates †o a method for the prevention or treatment of an infection by an enveloped virus, in particular of the Coronaviridae family, in an individual, comprising administering †o the individual an effective amount of a composition comprising a† leas† one me†hyl-cyclodex†rin.

The present invention also relates †o a method as defined above, wherein composition is administered in combination with a† leas† one other compound suitable for the prevention or treatment of an infection by an enveloped virus, in particular of the Coronaviridae family, more particularly by SARS-CoV-2.

The present invention also relates †o a pharmaceutical composition comprising: a† leas† one me†hyl-cyclodex†rin, and a† leas† one other compound suitable for the prevention or treatment of an infection by an enveloped virus, in particular of the Coronaviridae family, more particularly by SARS-CoV-2 and optionally a† leas† one pharmaceutically acceptable vehicle or excipient. Description of the invention

As intended herein, the word “comprising” is synonymous †o “include” or “contain”. When a subject-matter is said †o comprise one or several features, if is mean† †ha† other features than those mentioned can be comprised in the subjec†- matter. Conversely, the expression “constituted of” is synonymous †o “consisting of”. When a subject-matter is said †o consist of one or several features, it is mean† †ha† no other features than those mentioned are comprised in the subject-matter.

Methyl-cyclodextrin As intended herein a cyclodextrin is a cyclic polymer of D-glucopyranose units attached together by a- 1 ,4-linkages. a-D-glucopyranose is represented in formula (I) below:

The most common cyclodexfrins contain six, seven, or eight glucopyranose units and are respectively named a-cyclodex†rin (a-CD), b-cyclodexfrin (b-CD) and y- cyclodexfrin (y-CD).

The most common cyclodexfrins are represented in formula (II) below:

wherein n = 1 , 2 or 3.

The three-dimensional structure of cyclodexfrin is in the form of a truncated cone on the outside of which are the hydroxyl groups representing their highly hydrophilic par†. The interior of the cone or the cavity of cyclodextrins is made up of the hydrogen atoms borne by the C3 and C5 carbons and also of the oxygen atoms which participate in the glycosidic bond, thus conferring on them a nonpolar nature.

With a view †o improving the aqueous solubility of cyclodextrins, many derivatives have been synthesized by grafting various groups onto the hydroxyl groups or by substituting the hydroxyl groups by various groups. The hydroxyl groups of the glucopyranose units of cyclodextrins which are the most amenable †o grafting or substitution are borne by the C2, C3 and C6 carbons.

As intended herein a me†hyl-cyclodex†rin is a methyl ester of cyclodextrin, i.e. one or more methyl groups are esterified respectively on one or more hydroxyl groups of the glucopyranose units of the cyclodextrin, in particular those borne by the C2, C3 and C6 carbons. As intended herein, the hydroxyl groups are said †o be substituted, or esterified, by, or with, methyl groups. As intended herein, when a cyclodextrin is said †o be substituted, unless specified otherwise, i† is by one or methyl groups. Methyl- cyclodextrins as defined above can be obtained as described in International publication WOOl /36490, which is incorporated herein by reference.

Preferably, the a† leas† one me†hyl-cyclodex†rin defined above comprises or consists of a† leas† one me†hyl-p-cyclodex†rin.

Preferably, the a† leas† one me†hyl-cyclodex†rin, in particular me†hyl-p-cyclodex†rin, as defined above comprises or consists of one or more me†hyl-cyclodex†rins, in particular me†hyl-p-cyclodex†rins, having a degree of molarsubs†i†u†ion of between 0.05 and 1 .5, between 0.10 and 1 .40, between 0.10 and 1 .30, between 0.10 and 1 .20, between 0.15 and 1.40, between 0.15 and 1.30, between 0.15 and 1.20, between 0.20 and 1.40, between 0.20 and 1 .30, between 0.20 and 1 .20, between 0.20 and 1.10, between 0.25 and 1.40, between 0.25 and 1.30, between 0.25 and 1.20, between 0.25 and 1.10, between 0.15 and 0.90, between 0.15 and 0.80, between 0.25 and 1 .00, between 0.25 and 0.90, between 0.25 and 0.80, between 0.30 and 1.40, between 0.30 and 1.30, between 0.30 and 1 .20, between 0.30 and 1 .00, between 0.50 and 0.90, between 0.60 and 0.80, or of about 0.7.

More preferably, the a† leas† one me†hyl-cyclodex†rin, in particular methyl-b- cyclodextrin, as defined above comprises or consists of one or more methyl- cyclodextrins having a degree of molar substitution from 0.05 to 1 .5, in particular from 0.2 †o 1 .2, more particularly from 0.6 to 0.8, even more particularly of about 0.7.

As intended herein the expression “degree of molar substitution”, abbreviated MS, designates the number of hydroxyl groups substituted with a methyl group per glucopyranose uni† of the me†hyl-cyclodex†rin. I† should be noted †ha† the degree of molarsubs†i†u†ion (MS) is different from the degree of molecyj r substitution (DS), which corresponds †o the number of hydroxyl groups substituted with a methyl group per cyclodextrin molecule and which therefore takes into account the number of glucopyranose units constituting the me†hyl-cyclodex†rin.

The MS can be determined by numerous techniques well known †o one of skill in the ar†, which all yield similar or identical results. The MS can notably be determined by proton nuclear magnetic resonance (NMR), or by mass spectrometry (electrospray ionization mass spectrometry (ESI-MS) or matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS)). Although these techniques can be readily implemented by those skilled in the ar† without any particular guidance, optimal conditions for determining the MS of me†hyl-cyclodex†rins are described by way of example in the thesis by Romain JACQUET (2006) “Cyclodextrines hydrophiles: caracterisation et etude de leurs proprietes enantioselective et complexante. Utilisation de la chromatographie en phase liquide et de la spectrometrie de masse" [“Hydrophilic cyclodextrins: characterization and study of their enantioselective and complexing properties. Use of liquid chromatography and mass spectrometry”], Universite d’Orleans (downloadable from the URL: †el.archives-ouver†es.fr/†el- 00185542), which is incorporated herein by reference, in particular in Chapter 2, Par† B (pages 59 to 83). Preferably, the MS is determined by NMR, according †o the following method: the measurements are carried out at 25°C on an Advance DPX 250 MHz apparatus (Bruker, Rheinstetten, Germany). The calibration is performed with the D20 signal. The samples of methyl-cyclodextrin, and of native cyclodextrin, i.e. non-methylated cyclodextrin, are prepared at a concentration of 5 mg in 0.75 ml of D20. The solutions are evaporated to dryness under a nitrogen stream and then reconstituted in 0.75 ml of D20. This operation is repeated twice in order to ensure total exchange of the protons of the hydroxyl functions. The MS is calculated from the difference in integration between the spectrum of the native cyclodextrin and that of the methyl- cyclodextrin.

It should be noted that although the at least one methyl-cyclodextrin, in particular me†hyl-p-cyclodex†rin, used in accordance with the invention can be a pure product, it is usually a mixture of different methyl-cyclodextrins, in particular having various profiles of methylation. This is the case, by way of example, of the product KLEPTOSE® CRYSMEB (ROQUETTE), which has in particular the physicochemical properties as determined in the above-mentioned thesis by Romain JACQUET, in particular chapter 2, part B (pages 59 to 83). As such, the MS measured for a given methyl-cyclodextrin is generally an average of the substitutions which take place on all of the glucopyranose units of the entire mixture of methyl-cyclodextrins. This mixture may in particular contain residual native cyclodextrin, i.e. non-methylated cyclodextrin, but it is generally in negligible amounts, in particular less than 1% by dry weight relative to the total dry weight of the methyl-cyclodextrin, preferably less than 0.5%, more preferably less than 0.1%.

Preferably, at least 50% of methyl groups of the at least one methyl-cyclodextrin as defined above are substituted on an hydroxyl group borne by the C2 carbon of glucopyranose units, more preferably between 60% and 80%, typically about 75%. In parallel, the other methyl groups generally substitute the hydroxyl groups borne by the C3 and/or C6 carbons of the glucopyranose units.

Those skilled in the art know how to determine the distribution of the methyl groups on the hydroxyl groups of the glucopyranose unit of methyl-cyclodextrin, for example by NMR.

Preferably, methyl groups of the at least one methyl-cyclodextrin, in particular methyl- b-cyclodextrin, as defined above are substituted on an hydroxyl group borne by the C2 carbon of glucopyranose units, or by the C3 and/or C6 carbons of glucopyranose units, or by a combination of the C2, C3 and/or C6 carbons of glucopyranose units. Preferably, the at least one methyl-cyclodextrin as defined above comprises or consists of one or more me†hyl-p-cyclodex†rins selected from the group consisting of me†hyl-p-cyclodex†rins having methyl groups substituted on an hydroxyl group borne by the C2 carbon of glucopyranose units, me†hyl-p-cyclodex†rins having methyl groups substituted on an hydroxyl group borne by the C3 and/or C6 carbons of glucopyranose units, and me†hyl-p-cyclodex†rins substituted on an hydroxyl group borne by the C2, C3 and/or C6 carbons of glucopyranose units, said me†hyl-3- cyclodextrins having a degree of molar substitution between 0.4 and 0.8, preferably between 0.6 and 0.8, in particular about 0.7.

Preferably, the at least one methyl-cyclodextrin as defined above comprises or consists of one or more me†hyl-p-cyclodex†rins, in which at least 50% of the methyl groups are located at the level of the hydroxyl groups borne by the C2 carbon of glucopyranose units, preferably between 60% and 80%, typically about 75%, and have an MS of between 0.05 and 1 .5, preferably between 0.1 and 1 .4, preferably between 0.1 and 1.3, preferably between 0.2 and 1.2, preferably between 0.3 and 1.1 , preferably between 0.4 and 1 , preferably between 0.5 and 0.9, preferably between 0.4 and 0.8, preferably between 0.6 and 0.8, in particular about 0.7.

Preferably, the composition of at least one methyl-cyclodextrin as defined above comprises one or more me†hyl-p-cyclodex†rins selected from the group consisting of me†hyl-p-cyclodex†rins substituted on the hydroxyl borne by the C2 carbon of the glucopyranose units, me†hyl-p-cyclodex†rins substituted on the hydroxyl borne by the C3 and/or C6 carbon of the glucopyranose units, and me†hyl-p-cyclodex†rins substituted on the hydroxyl borne by the C2, C3 and/or C6, preferably C2 and C6, carbons of the glucopyranose units and having an MS of between 0.05 and 1.5, preferably of between 0.1 and 1.4, preferably between 0.1 and 1.3, preferably between 0.2 and 1 .2, preferably between 0.3 and 1.1 , preferably between 0.4 and 1 , preferably between 0.5 and 0.9, preferably between 0.6 and 0.8, for example about 0.7, in particular 0.68. For example, the at least one methyl-cyclodextrin as defined above can have an MS of between 0.10 and 1.40, between 0.10 and 1.30, between 0.10 and 1 .20, between 0.15 and 1 .40, between 0.15 and 1 .30, between 0.15 and 1 .20, between 0.20 and 1 .40, between 0.20 and 1 .30, between 0.20 and 1 .20, between 0.20 and 1.10, between 0.25 and 1.40, between 0.25 and 1.30, between 0.25 and 1.20, between 0.25 and 1.10, between 0.25 and 1 .00, between 0.25 and 0.90, between 0.25 and 0.80, between 0.30 and 1.40, between 0.30 and 1.30, between 0.30 and 1.20, between 0.30 and 1.00, between 0.50 and 0.90, between 0.60 and 0.80, or of about 0.7. Preferably, this composition of a† leas† one methyl cyclodextrin comprises a† leas† 50%, 60% or 75% of methyl groups substituted on the hydroxyl groups borne by the C2 carbon of glucopyranose units.

Preferably, the composition of a† leas† me†hyl-cyclodex†rin, in particular methyl-b- cyclodextrin, as defined above comprises a mixture of me†hyl-cyclodex†rins comprising a† leas† 50%, 60%, 70%, 80% or 90% of me†hyl-cyclodex†rins having an MS of between 0.2 and 1 .2. Preferably, a† leas† 40%, 50%, 60%, 70%, 80% or 90% of methyl- cyclodextrins have an MS of between 0.3 and 1 .1 . Preferably, a† leas† 30%, 40%, 50%, 60%, 70%, 80% or 90% of me†hyl-cyclodex†rins have an MS of between 0.5 and 0.9. Even more preferably, a† leas† 25%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of methyl- cyclodextrins have an MS of between 0.6 and 0.8.

The composition of a† leas† one me†hyl-cyclodex†rin, in particular methyl-b- cyclodextrin, as defined above, can be optionally prepared by adding various me†hyl-cyclodex†rins having defined MSs so as †o obtain a composition as defined above, or the composition can be obtained as a result of the synthesis of the methyl- cyclodextrin.

Preferably, the composition of a† leas† one methyl cyclodextrin, in particular methyl-b- cyclodextrin, as defined above has the following substitution profile, expressed as molar percentages:

0 to 5% of methyl^-cyclodextrins comprising 2 methyl groups (DS of 2);

5% to 15% of methyl^-cyclodextrins comprising 3 methyl groups (DS of 3);

20% to 25% of methyl^-cyclodextrins comprising 4 methyl groups (DS of 4);

25% to 40% of methyl^-cyclodextrins comprising 5 methyl groups (DS of 5);

15% to 25% of methyl^-cyclodextrins comprising 6 methyl groups (DS of 6);

5% to 15% of methyl^-cyclodextrins comprising 7 methyl groups (DS of 7);

0% to 5% of methyl^-cyclodextrins comprising 8 methyl groups (DS of 8).

The total sum of the percentages is generally about 100%, although the composition can optionally contain traces of me†hyl-cyclodex†rins of different DS, and also traces of native cyclodextrin, i.e. non-me†hyla†ed cyclodextrin.

The substitution profile of me†hyl-cyclodex†rins can be determined by any technique well known †o those skilled in the ar†, for example by ESI-MS or MALDI-TOF-MS. By way of example, optimal conditions for determining the substitution profile using these two methods are discussed in the abovementioned thesis by Romain JACQUET, in chapter 2, part B, points 1 1 .3 and 1 1 .2 (page 67 to 82) and in Appendix II.

Preferably, the composition of at least one methyl cyclodextrin, in particular methyl-b- cyclodextrin, as defined above is such that at least 50% of methyl groups are substituted on the hydroxyl groups borne by the C2 carbon of glucopyranose units, more preferably between 60% and 80%, typically about 75%, and has the following substitution profile, expressed as molar percentages:

0% to 5% of methyl^-cyclodextrins comprising 2 methyl groups (DS of 2);

5% to 15% of methyl^-cyclodextrins comprising 3 methyl groups (DS of 3);

20% to 25% of methyl^-cyclodextrins comprising 4 methyl groups (DS of 4);

25% to 40% of methyl^-cyclodextrins comprising 5 methyl groups (DS of 5);

15% to 25% of methyl^-cyclodextrins comprising 6 methyl groups (DS of 6);

5% to 15% of methyl^-cyclodextrins comprising 7 methyl groups (DS of 7);

0% to 5% of methyl^-cyclodextrins comprising 8 methyl groups (DS of 8).

The total sum of the above percentages is generally about 100%, although the composition can optionally contain traces of methyl-cyclodextrins of different DS, and also traces of native cyclodextrin, i.e. non-methylated cyclodextrin.

Besides, it possible to envision varying the proportions of or isolating particular methyl- cyclodextrins or groups of methyl-cyclodextrins, in particular according to their DS. Thus, preferably, the at least one methyl-cyclodextrin as defined above is a methyl-b- cyclodextrin which has a DS selected from an integer ranging from 2 to 8, in particular 2, 3, 4, 5, 6, 7 or 8.

Preferably, the at least one methyl-cyclodextrin as defined above is a methyl-b- cyclodextrin in which at least 50% of the methyl groups are substituted on the hydroxyl groups borne by the C2 carbon of the glucopyranose units, preferably between 60% and 80%, typically about 75%, and which has a DS chosen from an integer ranging from 2 to 8, in particular 2, 3, 4, 5, 6, 7 or 8.

Preferably, the at least one methyl-cyclodextrin, in particular methyl^-cyclodextrin, as defined above has an MS of between 0.1 and 0.3, in particular between 0.2 and 0.3, especially between 0.20 and 0.30. Preferably also, the at least one methyl- cyclodextrin, in particular methyl^-cyclodextrin, as defined above has an MS of between 0.3 and 0.5, especially between 0.30 and 0.50. Preferably also, the at least one methyl-cyclodextrin, in particular methyl^-cyclodextrin, as defined above has an MS of between 0.5 and 0.6, especially between 0.50 and 0.60. Preferably also, the at least one methyl-cyclodextrin, in particular methyl^-cyclodextrin, as defined above has an MS of between 0.6 and 0.7, especially between 0.60 and 0.70. Preferably also, the at least one methyl-cyclodextrin, in particular methyl^-cyclodextrin, as defined above has an MS of between 0.7 and 0.8, especially between 0.70 and 0.80. Preferably also, the at least one methyl-cyclodextrin, in particular methyl^-cyclodextrin, as defined above has an MS of between 0.8 and 0.9, especially between 0.80 and 0.90. Preferably also, the at least one methyl-cyclodextrin, in particular methyl-b- cyclodextrin, as defined above has an MS of between 0.9 and 1.1, especially between 0.90 and 1.10. Preferably also, the at least one methyl-cyclodextrin, in particular methyl^-cyclodextrin, as defined above has an MS of between 1.1 and 1 .2, especially between 1.10 and 1.20.

Preferably, the at least methyl-cyclodextrin as defined above is KLEPTOSE® CRYSMEB (ROQUETTE). The mass spectrometry analysis of the KLEPTOSE® CRYSMEB product, which is a methyl^-cyclodextrin, reveals in particular that it is a polydispersed product, comprising seven predominant methyl cyclodextrin groups, which differ from one another by their DS. This DS, which in theory can range from 0 to 21 for a methyl-b- cyclodextrin, ranges from 2 to 8 in the KLEPTOSE® CRYSMEB product. Besides, the MS of the KLEPTOSE® CRYSMEB product as determined by RMN in the above-mentioned thesis of Romain JACQUET is of about 0.7, more specifically 0.68.

Generally, the at least methyl-cyclodextrin as defined above has a reducing sugar content of less than 1 w†% by dry weight, preferably less than 0.5 w†%.

Optionally, the composition as defined above may also comprise a cyclodextrin, in particular a b-cyclodextrin, which is unsubstituted, and/or a cyclodextrin, in particular a b-cyclodextrin, which is substituted with sulfobutyl ether (SBE-), hydroxyethyl, hydroxypropyl (HP-), carboxymethyl, carboxyethyl, acetyl, triacetyl, succinyl, ethyl, propyl, butyl, sulfate groups, preferably sulfobutyl and hydroxypropyl groups, preferably with a degree of molar substitution of between 0.05 and 1 .5.

Virus

As intended herein, an enveloped virus is a virus that has an outer wrapping or envelope. This envelope comes from the infected cell, or host, in a process called "budding off." During the budding process, newly formed virus particles become "enveloped" or wrapped in an outer phospholipidic coat that is made from a small piece of the cell's plasma membrane.

Preferably, the virus as defined above is: an Herpesviridae virus, in particular Herpes simplex virus, varicella-zoster virus, cytomegalovirus, Epsfein-Barr virus, a Pleolipoviridae virus, in particular HHPV1 , HRPV1 , HGPV1 , His2V, a Togaviridae virus, in particular Rubella virus, alphavirus, an Arenaviridae virus, in particular Lymphocytic choriomeningitis virus, a Flaviviridae virus, in particular Dengue virus, hepatitis C virus (HCV), yellow fever virus, Zika virus, an Orfhomyxoviridae virus, in particular Influenzavirus A, influenzavirus B, influenzavirus C, isavirus, fhogofovirus, a Paramyxoviridae , in particular Measles virus, mumps virus, respiratory syncytial virus, Rinderpest virus, canine distemper virus, a Bunyaviridae virus, in particular California encephalitis virus, hantavirus, a Rhabdoviridae virus, in particular Rabies virus, a Filoviridae virus, in particular Ebola virus, Marburg virus, a Coronaviridae, in particular Coronavirus a Bornaviridae virus, in particular Borna disease virus, an Arferiviridae virus, in particular Arferivirus, equine arteritis virus a Retroviridae virus, in particular HIV, more particularly HIV-1 or HIV-2 an Hepadnaviridae virus, in particular hepatitis B virus (HBV),

Preferably, the enveloped virus is of the Coronaviridae family.

Preferably, the virus as defined above is of the Alphacoronavirus, Betacoronavirus, Deltacoronavirus, or Gammacoronavirus genus, more preferably of the Betacoronavirus genus, most preferably of the Sarbecovirus or the Merbecovirus sub genus.

Preferably also the virus as defined above is a human virus, i.e. a virus which can infect a human.

Preferably, the virus as defined above is selected from the group consisting of SARS- CoV, SARS-CoV-2, MERS-CoV and mutants or variants thereof.

Preferably, the virus as defined above is SARS-CoV-2, or a mutant or variant thereof. SARS-CoV-2 is notably described in Fuk-Woo Chan et al. (2020) Emerging Microbes & Infections 9:221-236, which is incorporated herein by reference, and is also named 2019-nCoV, HCoV-19, SARS2, COVID-19 virus, Wuhan coronavirus, Wuhan seafood market pneumonia virus, Human coronavirus 2019.

Preferably, the virus as defined above is SARS-CoV-2 and has the genomic sequence defined by NCBI Reference Sequence NCJD45512.2 (SEQ ID NO: 1 ), or the complementary thereof, or is a mutant or variant thereof.

As intended herein, a “mutant or variant” of a virus as defined above, or of a genomic sequence of a virus as defined above, has a genomic sequence or is a nucleotide sequence which has of leas† 85%, 90%, 95%, 96% 97%, 98%, 99% or 99,5% identify with the genomic sequence of the virus as defined above.

Mutant or variants of SEQ ID NO: 1 can in particular be found on the “NCBI virus” website by searching for SARS-CoV-2 †axid:2697049. A preferred variant of SARS-CoV- 2 is the D614G SARS-CoV-2 variant, which harbours an A-†o-G nucleotide mutation at position 23403 in SEQ ID NO: 1 . Preferred variant of SARS-CoV-2 may also harbour the E484K mutation and/or the N501 Y mutation.

As intended herein, a first nucleotide sequence “having at least X% identity” with a second nucleotide sequence, in particular differs from the second sequence by the insertion, the suppression or the substitution of at least one nucleotide. Besides, the percentage of identity between two nucleotide sequences is defined herein as the number of positions for which the bases are identical when the two sequences are optimally aligned, divided by the total number of bases of the longest of the two sequences. Two sequences are said to be optimally aligned when the percentage of identity is maximal. Besides, as will be clear to one of skill in the art, it may be necessary to add gaps in order to obtain an optimal alignment between the two sequences. In addition, when calculating the percentage of identity between an RNA nucleotide sequence and a DNA nucleotide sequence, an Uracile (U) base and a Thymine (T) base at the same position are considered to be identical.

As intended herein preventing or treating an infection by a enveloped virus, in particular of the Coronaviridae family, in an individual, encompasses preventing or treating the symptoms, disorders, syndromes, conditions or diseases, such as pneumonia or COVID-19, associated to the infection by the enveloped virus, in particular of the Coronaviridae family, more particularly by SARS-CoV-2. Individual

Preferably, the individual is a bird, such as a chicken, or a mammal, such as a human, a canine, in particular a dog, a feline, in particular a cat, an equine, a bovine, a porcine, a caprine, such a sheep or a goaf, or a camelidae, more preferably the individual is a human.

Preferably, the individual as defined above is a human aged 50 or more, more preferably 60 or more, even more preferably 70 or more and most preferably 80 or more.

Preferably, the individual as defined above is a male individual.

Preferably, the individual as defined above suffers from af leas† one other disease or condition, in particular selected from hypertension, diabetes, in particular type 2 diabetes, metabolic syndrome, a cardiovascular disease, in particular ischemic cardiomyopathy, a chronic respiratory disease, an aufo-immune disease or cancer. Preferably, the individual as defined above is overweight or obese.

According †o a usual definition a human individual is considered overweight if its Body Mass Index (BMI, body weigh† in kg relative †o the square of the heigh† in meters) is higher than or equal †o 25 kg/m² and less than 30 kg/m² and the individual will be said obese if his BMI is higher than or equal †o 30 kg/m². The individual according †o the invention may notably present with severe obesity, in particular characterized in human by a BMI higher than or equal to 35 kg/m².

More generally, it is preferred that the individual as defined above is a human and has a BMI higher than or equal to 25 kg/m², 26 kg/m², 27 kg/m², 28 kg/m², 29 kg/m², 30 kg/m², 31 kg/m², 32 kg/m², 33 kg/m², 34 kg/m², 35 kg/m² or 40 kg/m².

Besides, the individual as defined above may also have an abdominal obesity, corresponding in particular to a visceral adipose tissue excess. According to a usual definition a male human individual has an abdominal obesity if the abdominal perimeter is higher than or equal to 94 cm, in particular higher than 102 cm and a female human individual has an abdominal obesity if the abdominal perimeter is higher than or equal to 80 cm, in particular higher than 88 cm. The abdominal perimeter measure is well known to one of skilled in the art: abdomen circumference is thus preferably measured midway between the last floating rib and the top of the iliac crest in a standing individual in gentle expiration.

It is particularly preferred that the individual as defined above is a man and presents with an abdominal perimeter higher than or equal to 90 cm, 91 cm, 92 cm, 93 cm, 94 cm, 95 cm, 96 cm, 97 cm, 98 cm, 99 cm, 100 cm, 101 cm or 102 cm. I† is also preferred that the individual according †o the invention is a woman and presents with an abdominal perimeter higher than or equal to 75 cm, 76 cm, 77 cm, 78 cm, 79 cm, 80 cm, 81 cm, 82 cm, 83 cm, 84 cm, 85 cm, 86 cm, 87 cm or 88 cm.

Preferably, the individual according to the invention is afflicted with COVID-19 or is at risk of being afflicted with COVID-19.

Additional compound

Preferably, the other compound suitable for the prevention or treatment of an infection by a virus of the Coronaviridae family, in particular by SARS-CoV-2, is selected from the group consisting in chloroquine, remdesivir, hydroxychloroquine, ribavirin, penciclovir, favipravir, nafamostat, nitazoxanide, thalidomide, fingolimod, carrimycin, lopinavir/ritonavir, methylprednisolone, bevacizumab, N-ace†ylcys†eine, recombinant human interferon a ΐ b, arbidol, eculizumab, darunavir, cobicistat, meplazumab, bamlanivimab, tocilizumab, danoprevir, peginterferon alfa-2a, oseltamivir, ivermectin, colchicine, clofoctol, GS-441524, MK-71 1 , molnupiravir, intravenous immunoglobulins and pharmaceutically acceptable salt, ester or prodrug thereof; more preferably it is chloroquine and/or remdesivir, or molnupiravir, or pharmaceutically acceptable salts, esters or prodrugs thereof; and most preferably it is chloroquine phosphate.

Pharmaceutical composition

Preferably, the pharmaceutical composition as defined above comprises: at least one methyl-cyclodextrin as defined above, at least one other compound suitable for the prevention or treatment of an infection by a virus of the Coronaviridae family, in particular by SARS-CoV-2 as defined above, in particular chloroquine and/or remdesivir, or molnupiravir, or pharmaceutically acceptable salts, esters or prodrugs thereof, and optionally at least one pharmaceutically acceptable vehicle or excipient.

The at least one pharmaceutically acceptable vehicle or excipient may notably be selected from dispersants, solubilizing agents, stabilizers, preservatives, etc. Besides, pharmaceutically acceptable vehicle or excipient that can be used in formulations, in particular liquid and/or injectable formulations, are preferably selected from methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polysorbate 80, mannitol, gelatin, lactose, vegetable oils, acacia, liposomes, etc. It is also possible to envision a galenical form in which the me†hyl-cyclodex†rin as defined above is administered in a form complexed with a lipid substance, in particular a negatively charged lipid substance.

Preferably, the a† leas† one me†hyl-cyclodex†rin as defined above is in a solution, in particular a saline solution.

Administration

As intended herein “combined” or “in combination” means that the composition as defined above, is administered a† the same time than the additional compound as defined above, either together, i.e. a† the same administration site, or separately, or a† different times, provided that the time period during which the composition as defined above exerts its pharmacological effects on the individual and the time period during which the additional compound exerts its pharmacological effects on the individual, a† leas† partially intersect.

The compositions as defined above can be administered orally, parenterally, mucosally or cutaneously. The parenteral route preferably comprises subcutaneous, intravenous, intramuscular or in†raperi†oneal administration, although the latter is rather reserved for animals. The mucosal route preferably comprises nasal administration, pulmonary administration or administration via the rectal mucosa. The cutaneous route advantageously comprises the dermal route, in particular via a transdermal device, typically a patch.

The compositions as defined above can be formulated in the form of injectable suspensions, gels, oils, tablets, suppositories, powders, gel capsules, capsules, aerosols, etc., optionally by means of galenical forms or of devices which provide sustained and/or delayed release. For this type of formulation, an agent such as cellulose, carbonates or starches is advantageously used.

The compositions as defined above can be administered †o the individual as defined above a† a dose between 1 and 100 mg/kg, preferably between 20 and 70 mg/kg, even more preferably between 30 and 50 mg/kg, and even more preferably 40 mg/kg, of me†hyl-cyclodex†rin, in particular me†hyl-p-cyclodex†rin, as defined above, relative †o the total weigh† of the individual. Of course, those skilled in the ar† are able †o adjust the dose of me†hyl-cyclodex†rin, in particular me†hyl-p-cyclodex†rin, as defined above according †o the weigh† of the individual †o be treated. Preferably, the quantity of me†hyl-cyclodex†rin, in particular me†hyl-p-cyclodex†rin, as defined above, is administered to the individual as defined above a† a dose enabling †o reach an corporeal concentration, in particular a blood or plasma concentration, of methyl mefhyl-cyclodexfrin, in particular me†hyl-p-cyclodex†rin, below 10 mM, 5 mM, 3 mM, 2 mM, 1 mM or 500 mM. Preferably, the quantify of mefhyl-cyclodexfrin, in particular me†hyl-p-cyclodex†rin, as defined above, is administered †o the individual as defined above a† a dose enabling †o reach an corporeal concentration, in particular a blood or plasma concentration, of methyl mefhyl-cyclodexfrin, in particular mefhyl-b- cyclodexfrin, above 200 mM, 300 mM, 400 mM or 500 mM. Preferably, the quantify of mefhyl-cyclodexfrin, in particular mefhyl^-cyclodexfrin, as defined above, is administered †o the individual as defined above of a dose enabling †o reach an corporeal concentration, in particular a blood or plasma concentration, of methyl mefhyl-cyclodexfrin, in particular mefhyl^-cyclodexfrin, between 200 mM and 2 mM, or between 300 mM and 1 mM. The invention will be further described by the following non-limifing Examples.

EXAMPLES

Example 1

The efficacy of a mefhyl-p-cyclodexfrin with an average degree of molar substitution of 0.68 (KLEPTOSE® CRYSMEB EXP, ROQUETTE (France)) in inhibiting SARS-CoV-2 infection can be determined as described in Wang e† al. (2020) Cell Research (2020) 30:269-271 which is incorporated herein by reference.

Briefly, the cytotoxicity of the me†hyl-p-cyclodex†rin in Vero E6 cells (ATCC-1586) is first determined by the CCK8 assay.

Then, Vero E6 cells are infected with nCoV-2019Be†aCoV/Wuhan/WIV04/2019 at a multiplicity of infection (MOI) of 0.05 in the presence of varying concentrations of the me†hyl-p-cyclodex†rins. PBS is used in the controls.

Efficacy is evaluated by quantification of viral copy numbers in the cell supernatant via quantitative real-time RT-PCR (qRT-PCR) and confirmed with visualization of virus nucleoprotein (NP) expression through immunofluorescence microscopy at 48 h post infection (p.i.) (cytopathic effect is not obvious at this time point of infection). The half- maximal effective concentration (ECso) is then determined.

Example 2

The effect of a me†hyl-p-cyclodex†rin with an average degree of molar substitution of 0.68 (KLEPTOSE® CRYSMEB EXP, ROQUETTE (France)) on the replication cycle of SARS- Cov-2 has been determined as follows.

1 . Protocol

Cell lines: lung cancer A549 stably transfected with a lentiviral construct bearing the human ACE2 receptor cultured in DMEM with 10% serum and 1% penicillin/streptomycin.

Format: 384 well plate

MOI (multiplicity of infection) = 0,1 , SARS-CoV-2 Total incubation time: 72 hours

Positive control compound for viral replication used: remdesivir 10 mM Positive control compound for cytotoxicity used: camtothecine 10 mM Negative control: DMSO 0,5% Five concentration of the mefhyl-p-cyclodexfrin in triplicate were used: 3000 mM, 1000 mM, 300 mM, 100 mM, and 30 mM.

Cells (50% confluency) were firs† preincubated with me†hyl-p-cyclodex†rin 2h before infection with the virus for 1 h.

The inoculum was then removed and 40 mί of medium with the drug were added on the cells.

After 72h of incubation, the supernatant was recovered and the measurement of viral replication was carried ou† by quantitative RT-PCR in the presence and absence of drugs.

Detection: supernatant PCR-N gene region: 5’-TAATCAGACAAGGAACTGATTA-3 (forward) (SEQ ID NO: 2) and 5’-CGAAGGTGTGACTTCCATG-3’ (reverse) (SEQ ID NO: 3); Luna Universal One-step RT- qPCR ki† (NEB) in an applied biosystems QuantStudio thermocycler. The quantity of viral genomes is expressed as PFU (plaque forming uni†) equivalents, and was calculated by performing a standard curve with RNA derived from a viral stock with a known viral †i†er (plaque forming uni†).

In parallel, cell viability was assessed after 72h incubation with me†hyl-p-cyclodex†rin using the CellTiter Glo ki† from Promega which measures the cellular ATP concentration of live cells.

Raw data are normalized against appropriate negative (0%) ad positive (100%) controls and are expressed in % of viral replication inhibition or % cytotoxicity.

The curve fit is performed using the variable Plill Slope model or the four-parameter logistic curve:

(Maximum response-Baseline response) Response = Baseline response + _1+lo(L0gEc₅o-log_Concentration).Hillsiope where:

Response is the measured response on the Y axis;

Baseline response is the maximum response a† the bottom of the plateau; Maximum response is the maximum response a† the top of the plateau; IC50 is the concentration at 50% response;

Concentration is the measures drug concentration on the X axis;

Hill Slope is the Hill coefficient that describes the steepness of the curve. 2. Results

The results are summarized in the fable below:

Claims

1. A composition comprising at least one methyl-cyclodextrin for use in a method of prevention or treatment of an infection by an enveloped virus in an individual.

2. The composition for use according †o claim 1 , wherein the a† leas† one methyl- cyclodextrin comprises or consists of a† leas† one me†hyl-p-cyclodex†rin.

3. The composition for use according †o claim 1 or 2, wherein the a† leas† one methyl- cyclodextrin comprises or consists of one or more me†hyl-cyclodex†rins having a degree of molar substitution from 0.05 to 1.5, in particular from 0.2 †o 1.2, more particularly from 0.4 †o 0.8.

4. The composition for use according †o any of claims 1 †o 3, wherein methyl groups of the a† leas† one methyl-cyclodextrin are substituted on an hydroxyl group borne by the C2 carbon of glucopyranose units, or by the C3 and/or C6 carbons of glucopyranose units, or by a combination of the C2, C3 and/or C6 carbons of glucopyranose units.

5. The composition for use according †o any of claims 1 †o 4, wherein the a† leas† one methyl-cyclodextrin comprises or consists of one or more me†hyl-p-cyclodex†rins selected from the group consisting of me†hyl-p-cyclodex†rins having methyl groups substituted on an hydroxyl group borne by the C2 carbon of glucopyranose units, me†hyl-p-cyclodex†rins having methyl groups substituted on an hydroxyl group borne by the C3 and/or C6 carbons of glucopyranose units, and me†hyl-p-cyclodex†rins substituted on an hydroxyl group borne by the C2, C3 and/or C6 carbons of glucopyranose units, said me†hyl-p-cyclodex†rins having a degree of molar substitution between 0.4 and 0.8.

6. The composition for use according †o any of claims 1 †o 5, wherein a† leas† 50% of methyl groups of the a† leas† one methyl-cyclodextrin are substituted on an hydroxyl group borne by the C2 carbon of glucopyranose units.

7. The composition for use according †o any of claim 1 to 6, wherein the virus is of the Coronaviridae family, more particularly of the Betacoronavirus genus.

8. The composition for use according †o any of claim 1 to 7, wherein the virus is selected from the group consisting of SARS-CoV, SARS-CoV-2, MERS-CoV and mutants or variants thereof.

9. The composition for use according †o any of claim 1 †o 8, wherein the virus is SARS- CoV-2, or a mutant or variant thereof.

10. The composition for use according †o any of claims 1 †o 9, wherein the individual is aged 50 or more.

11. The composition for use according †o any of claims 1 to 10, wherein the individual suffers from af leas† one other disease or condition, in particular selected from hypertension, diabetes, a cardiovascular disease, a chronic respiratory disease, or cancer.

12. The composition for use according †o any of claims 1 to 1 1 , in combination with a† leas† one other compound suitable for the prevention or treatment of an infection by an enveloped virus.

13. The composition for use according †o any of claims 1 to 12, in combination with molnupiravir, or pharmaceutically acceptable salts, esters or prodrugs thereof.

14. A pharmaceutical composition comprising: a† leas† one me†hyl-cyclodex†rin as defined in any one of claims 1 †o 6, and a† leas† one other compound suitable for the prevention or treatment of an infection by an enveloped virus and optionally a† leas† one pharmaceutically acceptable vehicle or excipient.

15. A pharmaceutical composition according †o claim 14, comprising: a† leas† one me†hyl-cyclodex†rin as defined in any one of claims 1 †o 6, molnupiravir, or pharmaceutically acceptable salts, esters or prodrugs thereof, and optionally at least one pharmaceutically acceptable vehicle or excipient.