GB2593661A - Method of suppressing HIV-1 latent provirus activation and replication - Google Patents

Abstract

The agonists of RNA adenosine N-6 methylation (M6A) include small molecule derivatives of piperidine carboxylic acids and esters, 2-piperidinone carboxylic acids and esters, 1, 4-diazacyclohexane carboxylic acids and esters and 1, 3-diazacyclohexane carboxylic acids and esters, that are provided for suppression of HIV-1 provirus activation and replication of emerged virus genome by activation of the RNA methyltransferase complex METTL3/METTL14. In some embodiments, the compound has binding and/or activation for a METTL3/METTL14/WTAP complex. N-6 methylation agonists are also claimed to have suppress other lentiviruses such as HTLV-1

Description

I

METHOD OF SUPPRESSING HIV-1 LATENT proVIRUS ACTIVATION AND REPLICATION Inventors: Simona Se/berg, Eva 2usinaite, Andres Merits, Neinar Seli, Mati Karelson Assignee: Chemestmed, Ltd.

TECHNICAL FIELD

Methods and compounds are reported that specifically suppress HIV-1 provirus activation and replication of emerged virus genome by activation of the RNA methyltransferase complex METTL3/METTL14. In some embodiments, the compound has binding and/or activation for a METTL3/METTL14/VVTAP complex.

BACKGROUND ART

The presently disclosed subject matter generally relates to the suppression of the latent HIV-1 provirus using the epitranscriptomic regulation of the ribonucleic acid (RNA) methylation.

Chemical modifications of RNA have been identified to have an impact on several critical cellular functions, such as proliferation, survival and differentiation, mostly through regulation of RNA stability (Helm et al., 2017). The most abundant modification in eukaryotic messenger RNA is N6-methyladenosine (m6A) (Roundtree et al., 2017). It has been shown that m6A modifications of RNA affect its splicing, intracellular distribution, translation, and cytoplasmic degradation, playing thus a crucial role in regulating cell differentiation, neuronal signaling, carcinogenesis and immune tolerance (Maity et al., 2016). The m6A presence in RNA is regulated by specific enzymes, i.e. the RNA methyltransferases, RNA methylases and RNA reader proteins.

The modification of the viral RNAs by methylation of the amino-group at 6-position of adenosine (m6A) has been known for some time (Beemon et al, 1977). It has been shown that the presence of m6A is regulating the HIV-1 RNA viral replication and gene expression (Kennedy et al., 2016; Lichinchi et al., 2016, Tirumuru, et al, 2016; Rana, 2018).

The methylation of the adenosine is dynamically regulated in mammalian cells by RNA methyltransferases or "writers", demethylases or "erasers" and m6A recognizing proteins or "readers". The N6-methylation of adenosine is catalyzed by a 200 kDa methyltransferase heterodimer complex consisting of the Methyltransferase-Like Protein 3 (METTL3), METTL14 and the associated proteins Wilms Tumor 1 Associated Protein (VVTAP), RBM15/RBM15B and KIAA1429 (Liu et al, 2014; Meyer et al, 2017). METTL3 is a S-adenosylmethionine (SAM) dependent RNA m6A methyltransferase, while METTL14 together with RBM15/RBM15B, plays an important role in substrate recognition and binding (Wang, P, et al, 2016; Wang, X, et al, 2016; Patil et al, 2016). The primary function of WTAP is to localize METTL3 and METTL14 to nuclear speckles. It has been shown that VVTAP depletion causes loss of METTL3 and METTL14 localization from these speckles and loss of m6A formation in mRNA (Ping et al. 2014). Thus, VVTAP maintains METTL3 in speckles to efficiently methylate mRNA.

Recently, we have reported the discovery of the small-molecule activators of the RNA m6A methyltransferase METTL3/METTL14/VVTAP complex (Selberg et al, 2019). These activators of the m6A writer complex provide the first upstream means for increasing cellular m6A amounts. Contrary to FTO or AlkBH5 inhibitors that rely on the baseline activity of m6A writing to be effective, these small molecule m6A writer activators can help, for example, targeted guidance of cells to specific phenotypes.

HIV-1 belongs to family Retroviridae, genus Lentivirus. It is causative agent of AIDS. As a retrovirus HIV-1 had diploid RNA genome synthesized by cellular RNA polymerase II and modified by cellular RNA modification machinery. In infected cells the RNA is converted to complementary DNA (cDNA) that is integrated to host cell genome; the integrated cDNA copy of a retrovirus genome is known as provirus. In general, retrovirus provirus contains two promoter regions, one located at left and one at right side of the coding sequences. These elements are often referred to as long terminal repeats (LTRs). In general, transcriptional activity from left LTR supresses promoter activity of the LTR located at right from coding sequence of the virus. Removal or inactivation of left promoter typically results in activation of the promoter located at right from the coding sequences (Maartens et al, 2014).

HIV-1 promoter has complex regulation; it depends from host transcriptional factors and virus encoded proteins, mainly tat and rev. Tat regulates the activity of promoter acting as agent facilitating proceeding of RNA polymerase II from initiation of transcription to elongation. Rev regulates the time how fast the transcripts are transported from nucleus to cytoplasm. Such complex regulation, involving host and virus encoded factors, are characteristic for retroviruses collectively known as "complex retroviruses" (Cavallari et al, 2011).

From complex retroviruses human T-cell lymphotropic virus 1 (HTLV-1) is wide spread with up to 10 million people infected. Unlike HIV-1 HTLV-1 does not cause death of infected cells; instead it is an oncogenic virus causing aggressive cancer called adult T-cell lymphoma (ATL). Gene expression from HTLV-1 promoter is regulated by host factors and virus encoded proteins tax and rex. Unlike HIV-1 HTLV-1 is known to make relatively low number of virions (Martinez et al, 2019).

Many retroviruses are known to infect other vertebrate hosts, including domestic species such as cats (for example feline immunodeficiency virus) and cattle (bovine leukemia virus) (Garcia-Etxebarria et al, 2014)). Retroviruses are also common in non-human primates and have potential for host switches, an event that resulted in appearance of HIV-1 about 100 years ago.

Activation of retrovirus promoter is a key event in at least two processes associated with diseases in humans and animals. First, activation of promoter triggers virus gene expression, production of virus genome and, consequently, structural protein expression, virion formation and release. Thus, it is a key event of spread of retrovirus infection and, in case of HIV-1, causing AIDS. Controlling this process offers multiple opportunities to control retrovirus infection, pathogenesis and spread.

Second, activation of promoter may trigger abnormal expression of cellular and/or viral proteins that promote cell division. These proteins are collectively known as onco-proteins (White et al, 2014). Thus, activity/activation of retrovirus promoter has direct link to development of cancer, including ATL.

In the present application, we have studied the activity of the small-molecule activators of the RNA m6A methyltransferase METTL3/METTL14/VVTAP complex on the HIV-1 provirus activation and subsequent virus replication, virion formation and release. In parallel, we monitored the dynamics of the m6A as influenced by the activation of the m6A methylation in both HIV-1 and cellular RNA.

SUMMARY OF INVENTION

The present invention is related to a method to suppress the retrovirus provirus activation and subsequent replication (virion formation) through the activation of the RNA m6A methyltransferase METTL3/METTI14/VVTAP complex. It has been exemplified using HIV-1 provirus as model but includes also proviruses of other retroviruses. The invention is also related to suppression of LTR promoter of HIV-1 and that of other retroviruses. Also disclosed are the compounds, or salts or esters thereof, which can suppress the HIV-1 provirus activation and subsequent replication.

The "summary of invention" heading is not intended to be restrictive or limiting. The invention also includes all aspects described in the detailed description or figures as originally filed. The original claims appended hereto also define aspects that are contemplated as the invention and are incorporated into this summary by reference.

In addition to the foregoing, the invention includes, as an additional aspect, all embodiments of the invention narrower in scope in any way than the variations specifically mentioned above. For example, although aspects of the invention may have been described by reference to a genus or a range of values for brevity, it should be understood that each member of the genus and each value or sub-range within the range is intended as an aspect of the invention. Likewise, various aspects and features of the invention can be combined, creating additional aspects which are intended to be within the scope of the invention. Although the applicant(s) invented the full scope of the claims appended hereto, the claims appended hereto are not intended to encompass within their scope the prior art work of others. Therefore, in the event that statutory prior art within the scope of a claim is brought to the attention of the applicants by a Patent Office or other entity or individual, the applicant(s) reserve the right to exercise amendment rights under applicable patent laws to redefine the subject matter of such a claim to specifically exclude such statutory prior art or obvious variations of statutory prior art from the scope of such a claim.

Variations of the invention defined by such amended claims also are intended as aspects of the invention.

BRIEF DESCRIPTION OF DRAWINGS

The present invention is disclosed further with references to accompanying drawing where: FIG 1 illustrates HIV-1 virus level measured by content of HIV-1 p24 in cell culture medium by ELISA (T, 0D450) after treatment with the RNA m6A methyltransferase METTL3/METTL14/VVTAP activators at different compound concentrations (a) Compound (VIII); (b) compound (IX); (c) compound (X).

DETAILED DESCRIPTION OF INVENTION

Disclosed herein are compounds and methods of suppressing the retrovirus, exemplified by HIV-1, provirus activation and subsequent HIV-1 replication through activation of the RNA m6A methyltransferase METTL3/METTL14/VVTAP complex. In some variations of the invention, the compound is administered in a composition that also includes one or more pharmaceutically acceptable diluents, adjuvants, or carriers.

The compound can be a small molecule. In some embodiments, HIV-1 latent provirus suppressing agonist of RNA adenosine N-6 methylation has a structure of Formula (I), HI (I) wherein: R1 and R2 are independently selected from the group consisting of H, alkyl, acyl,; or a pharmaceutically acceptable salt thereof.

In some embodiments, HIV-1 latent provirus suppressing agonist of RNA adenosine N-6 methylation has a structure of Formula (II) wherein: R1 and R2 are independently selected from the group consisting of H, alkyl, aryl, acyl,; or a pharmaceutically acceptable salt thereof.

In some embodiments, HIV-1 latent provirus suppressing agonist of RNA adenosine N-6 methylation has a structure of Formula (III) R2 wherein: R1 and R2 are independently selected from the group consisting of H, alkyl, aryl, acyl,; or a pharmaceutically acceptable salt thereof.

In some embodiments, HIV-1 latent provirus suppressing agonist of RNA adenosine N-6 methylation has a structure of Formula (IV) (IV) wherein: R1 and R2 are independently selected from the group consisting of H, alkyl, aryl, acyl,; or a pharmaceutically acceptable salt thereof.

In some embodiments, HIV-1 latent provirus suppressing agonist of RNA adenosine N-6 methylation has a structure of Formula (V) (V) wherein: R1 and R2 are independently selected from the group consisting of H, alkyl, acyl,; or a pharmaceutically acceptable salt thereof.

In some embodiments, HIV-1 latent provirus suppressing agonist of RNA adenosine N-6 methylation has a structure of Formula (VI) (VI) wherein: R1 and R2 are independently selected from the group consisting of H, alkyl, acyl,; or a pharmaceutically acceptable salt thereof.

In some embodiments, HIV-1 latent provirus suppressing agonist of RNA adenosine N-6 methylation has a structure of Formula (VII)

RI

wherein: R1 is independently selected from the group consisting of consisting of H, alkyl, aryl, acyl,; or a pharmaceutically acceptable salt thereof.

In some embodiments, HIV-1 latent provirus suppressing agonist of RNA adenosine N-6 methylation has a structure of Formula (VIII) (VIII) or a pharmaceutically acceptable salt thereof.

In some embodiments, HIV-1 latent provirus suppressing agonist of RNA adenosine N-6 methylation has a structure of Formula (IX) (IX) or a pharmaceutically acceptable salt thereof.

In some embodiments, HIV-1 latent provirus suppressing agonist of RNA adenosine N-6 methylation has a structure of Formula (X) 1FI (X) or a pharmaceutically acceptable salt thereof.

As used herein, the term "alkyl" refers to straight chained and branched hydrocarbon groups containing carbon atoms, typically methyl, ethyl, and straight chain and branched propyl and butyl groups. Unless otherwise indicated, the hydrocarbon group can contain up to 20 carbon atoms. The term "alkyl" includes "bridged alkyl," i.e., a C.sub.6-C.sub.16 bicyclic or polycyclic hydrocarbon group, for example, norbornyl, adamantyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, or decahydronaphthyl. Alkyl groups optionally can be substituted, for example, with hydroxy (OH), halo, amino, and sulfonyl. An "alkoxy" group is an alkyl group having an oxygen substituent, e.g., --O-alkyl.

The term "alkenyl" refers to straight chained and branched hydrocarbon groups containing carbon atoms having at least one carbon-carbon double bond. Unless otherwise indicated, the hydrocarbon group can contain up to 20 carbon atoms. Alkenyl groups can optionally be substituted, for example, with hydroxy (OH), halo, amino, and sulfonyl.

As used herein, the term "alkylene" refers to an alkyl group having a further defined substituent. For example, the term "alkylenearyl" refers to an alkyl group substituted with an aryl group, and "alkyleneamino" refers to an alkyl groups substituted with an amino group. The amino group of the alkyleneamino can be further substituted with, e.g., an alkyl group, an alkylenearyl group, an aryl group, or combinations thereof. The term "alkenylene" refers to an alkenyl group having a further defined substituent.

As used herein, the term "aryl" refers to a monocyclic or polycyclic aromatic group, preferably a monocyclic or bicyclic aromatic group, e.g., phenyl or naphthyl. Unless otherwise indicated, an aryl group can be unsubstituted or substituted with one or more, and in particular one to four groups independently selected from, for example, halo, alkyl, alkenyl, OCF.sub.3, NO.sub.2, CN, NC, OH, alkoxy, amino, CO.sub.2H, CO.sub.2alkyl, aryl, and heteroaryl. Exemplary aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, chlorophenyl, methylphenyl, methoxyphenyl, trifluoromethylphenyl, nitrophenyl, 2,4-methoxychlorophenyl, and the like. An "aryloxy" group is an aryl group having an oxygen substituent, e.g., --0-aryl.

As used herein, the term "acyl" refers to a carbonyl group, e.g., C(0). The acyl group is further substituted with, for example, hydrogen, an alkyl, an alkenyl, an aryl, an alkenylaryl, an alkoxy, or an amino group. Specific examples of acyl groups include, but are not limited to, alkoxycarbonyl (e.g., C(0)--Oalkyl); aryloxycarbonyl (e.g., C(0)--OaryI); alkylenearyloxycarbonyl (e.g., C(0)--OalkylenearyI); carbamoyl (e.g., C(0)--NH.sub.2); alkylcarbamoyl (e.g., C(0)--NH(alkyl)) or dialkylcarbamoyl (e.g., C(0)--NH(alkyl).sub.2).

As used herein, the term "amino" refers to a nitrogen containing substituent, which can have zero, one, or two alkyl, alkenyl, aryl, alkylenearyl, or acyl substituents. An amino group having zero substituents is --NH.sub.2.

As used herein, the term "halo" or "halogen" refers to fluoride, bromide, iodide, or chloride As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid or inorganic acid. Examples of pharmaceutically acceptable nontoxic acid addition salts include, but are not limited to, salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, lactobionic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hem isulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.

EXAMPLES

The following Examples have been included to provide illustrations of the presently disclosed subject matter. In light of the present disclosure and the general level of skill in the art, those of skill will appreciate that the following Examples are intended to be exemplary only and that numerous changes, modifications and alterations can be employed without departing from the spirit and scope of the presently disclosed subject matter.

Example 1. Compounds and cell lines. Compounds Methyl 6-methylpiperidine-3-carboxylate (VII) (ArkPharm, Inc., Catalog Number: AK103663, Purity > 95%). Methyl piperazine-2-carboxylate (IX) (ChemDiv, Inc., Catalog Number: FF20-0374, Purity > 90%). Ethyl 2-oxopiperidine-3-carboxylate (X) (Enamine, Ltd., Catalog Number Z397585734, Purity > 90%).

Ce// lines.

ACH-2 cell line was obtained through the NIH AIDS Reagent Program, Division of AIDS, NIAID, NIH: ACH-257, 58 from Dr. Thomas Folks. ACH-2 cells were grown in Roswell Park Memorial Institute medium 1640 (RPM! 1640) supplemented with 25 mM HEPES, 0.3 g/L L-Glutamine, 10% heat-inactivated fetal bovine serum (FBS) and Pen/Strep.

Example 2. Methods

Here, 2x 105 ACH-2 cells infected with latent HIV-1 were seeded in 200 pL on a 96-well plate. The induced cells were incubated for 48 h with added compounds at given concentrations (0.5% MilliQ water was used as a vehicle control), and subsequently, the HIV-1 containing media was collected. The amount of HIV-1 p24 protein that was released into the media was measured using HIV1 p24 ELISA Kit (Abcam plc).

Example 3. Effect of RNA methyltransferase complex METTL3/METTL14/VVTAP activators on the HIV-1 latent provirus activation and virus replication.

The effect of the METTL3/METTL14/VVTAP activators on the HIV-1 provirus activation and virus replication was measured using p24 ELISA assay. The level in the virus production depends on the concentration of the activator compounds (VIII), (IX) and (X) (Figures 1(a), 1(b) and 1(c), respectively). For the three active compounds, significant suppression in the provirus activation and virus replication was detected at 1. . 100 pM concentration range.

A method of suppressing the HIV-1 provirus activation and subsequent infectious virion formation and release by using agonists of RNA adenosine N-6 methylation, wherein the agonists of RNA adenosine N-6 methylation are activators of the RNA methyltransferase METTL3/METTL14/VVTAP complex.

A method of suppressing the HIV-1 LTR promoter activity by using agonists of RNA adenosine N-6 methylation, wherein the agonists of RNA adenosine N-6 methylation are activators of the RNA methyltransferase METTL3/METTL14/VVTAP complex.

A method of suppressing the activation of proviruses of other lentiviruses infecting humans and subsequent infectious virion formation and release by using agonists of RNA adenosine N-6 methylation, wherein the agonists of RNA adenosine N-6 methylation are activators of the RNA methyltransferase METTL3/METTL14/VVTAP complex.

A method of suppressing the activation of proviruses of other lentiviruses infecting non-humans species and subsequent infectious virion formation and release by using agonists of RNA adenosine N-6 methylation, wherein the agonists of RNA adenosine N-6 methylation are activators of the RNA methyltransferase METTL3/METTL14/VVTAP complex.

A method of suppressing the activation of proviruses and subsequent infectious virion formation and release of other retroviruses infecting humans including but not limited to HTLV-1 by using agonists of RNA adenosine N-6 methylation, wherein the agonists of RNA adenosine N-6 methylation are activators of the RNA methyltransferase METTL3/METTL14/VVTAP complex.

A method of suppressing the HTLV-1 LTR promoter activity by using agonists of RNA adenosine N-6 methylation, wherein the agonists of RNA adenosine N-6 methylation are activators of the RNA methyltransferase METTL3/METTL14NVTAP complex.

A method of suppressing the activation of proviruses of other retroviruses infecting 15 non-humans species by using agonists of RNA adenosine N-6 methylation, wherein the agonists of RNA adenosine N-6 methylation are activators of the RNA methyltransferase METTL3/METTL14/VVTAP complex The agonist of RNA adenosine N-6 methylation has a structure of Formula (I) C. (I) wherein: R1 and R2 are independently selected from the group consisting of H, alkyl, aryl, acyl; or a pharmaceutically acceptable salt thereof.

The agonist of RNA adenosine N-6 methylation has a structure of Formula (II) wherein: R1 and R2 are independently selected from the group consisting of H, alkyl, aryl, acyl,; or a pharmaceutically acceptable salt thereof.

The agonist of RNA adenosine N-6 methylation has a structure of Formula (II) wherein: R1 and R2 are independently selected from the group consisting of H, alkyl, aryl, acyl; or a pharmaceutically acceptable salt thereof.

The agonist of RNA adenosine N-6 methylation has a structure of Formula (IV) (IV) wherein: R1 and R2 are independently selected from the group consisting of H, alkyl, aryl, acyl; or a pharmaceutically acceptable salt thereof.

The agonist of RNA adenosine N-6 methylation has a structure of Formula (V) (V) wherein: R1 and R2 are independently selected from the group consisting of H, alkyl, aryl, acyl; or a pharmaceutically acceptable salt thereof.

The agonist of RNA adenosine N-6 methylation has a structure of Formula (VI) (VI) wherein: R1 and R2 are independently selected from the group consisting of H, alkyl, acyl; or a pharmaceutically acceptable salt thereof.

The agonist of RNA adenosine N-6 methylation has a structure of Formula (VII)

NH (VII)

wherein: R1 is independently selected from the group consisting of consisting of H, alkyl, aryl, acyl, or a pharmaceutically acceptable salt thereof.

The agonist of RNA adenosine N-6 methylation has a structure of Formula (VIII) zie H. ._,D4H (VIII) The agonist of RNA adenosine N-6 methylation has a structure of Formula (IX)

NH (IX)

The agonist of RNA adenosine N-6 methylation has a structure of Formula (X) (X) A pharmaceutical composition comprising the compound of the agonist of RNA adenosine N-6 methylation having a structure according to any of the Formulas (I) -(X) and a pharmaceutically acceptable excipient.

A vaccine composition comprising the compound of the agonist of RNA adenosine N6 methylation having a structure according to any of the Formulas (I) -(X), a vaccine adjuvant, and an immunogenic agent.

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Claims (20)

1. Claims 1 A compound comprising agonists of RNA adenosine N-6 methylation for use in suppressing the HIV-1 provirus activation and subsequent infectious virion formation and release.
2. 2. A compound comprising agonists of RNA adenosine N-6 methylation for use in suppressing the HIV-1 LTR promoter activity.
3. 3. A compound comprising agonists of RNA adenosine N-6 methylation for use in suppressing the activation of proviruses of other lentiviruses infecting humans and subsequent infectious virion formation and release.
4. 4. A compound comprising agonists of RNA adenosine N-6 methylation for use in suppressing the activation of proviruses of other lentiviruses infecting non-humans species and subsequent infectious virion formation and release.
5. 5. A compound comprising agonists of RNA adenosine N-6 methylation for use in suppressing the activation of proviruses and subsequent infectious virion formation and release of other retroviruses infecting humans including but not limited to HTLV-1.
6. 6. A compound comprising agonists of RNA adenosine N-6 methylation for use in suppressing the HTLV-1 LTR promoter activity.
7. 7. A compound comprising agonists of RNA adenosine N-6 methylation for use in suppressing the activation of proviruses of other retroviruses infecting non-humans species.
8. 8. The compound according to any of claims 1-7, wherein the agonists of RNA adenosine N-6 methylation are activators of the RNA methyltransferase METTL3/METTL14/VVTAP complex.
9. 9. The compound according to any of claims 1-7, wherein the agonist of RNA adenosine N-6 methylation has a structure of Formula (I) r1^ (I) wherein: R1 and R2 are independently selected from the group consisting of H, alkyl, aryl, acyl; or a pharmaceutically acceptable salt thereof.
10. 10. The compound according to any of claims 1-7, wherein the agonist of RNA adenosine N-6 methylation has a structure of Formula (II) wherein. R1 and R2 are independently selected from the group consisting of H, alkyl, aryl, acyl,; or a pharmaceutically acceptable salt thereof.
11. 11 The compound according to any of claims 1-7, wherein the agonist of RNA adenosine N-6 methylation has a structure of Formula (III) RI, NH 0 (III) wherein: R1 and R2 are independently selected from the group consisting of H, alkyl, aryl, acyl; or a pharmaceutically acceptable salt thereof.
12. 12. The compound according to any of claims 1-7, wherein the agonist of RNA adenosine N-6 methylation has a structure of Formula (IV) (IV) wherein: R1 and R2 are independently selected from the group consisting of H, alkyl, aryl, acyl; or a pharmaceutically acceptable salt thereof.
13. 13. The compound according to any of claims 1-7, wherein the agonist of RNA adenosine N-6 methylation has a structure of Formula (V) (V) wherein: R1 and R2 are independently selected from the group consisting of H, alkyl, aryl, acyl; or a pharmaceutically acceptable salt thereof.
14. 14. The compound according to any of claims 1-7, wherein the agonist of RNA adenosine N-6 methylation has a structure of Formula (VI) (VI) wherein: R1 and R2 are independently selected from the group consisting of H, alkyl, aryl, acyl, or a pharmaceutically acceptable salt thereof.
15. 15. The compound according to any of claims 1-7, wherein the agonist of RNA adenosine N-6 methylation has a structure of Formula (VII) wherein: R1 is independently selected from the group consisting of consisting of H, alkyl, aryl, acyl; or a pharmaceutically acceptable salt thereof.
16. 16. The compound according to any of claims 1-7, wherein the agonist of RNA adenosine N-6 methylation has a structure of Formula (VIII) (VIII)
17. 17. The compound according to any of claims 1-7, wherein the agonist of RNA adenosine N-6 methylation has a structure of Formula (IX) (IX)
18. 18. The compound according to any of claims 1-7, wherein the agonist of RNA adenosine N-6 methylation has a structure of Formula (X) (X)
19. 19. A pharmaceutical composition comprising the compound of any one of claims 818 and a pharmaceutically acceptable excipient.
20. 20. A vaccine composition comprising the compound of any one of claims 8-18, a vaccine adjuvant, and an immunogenic agent.