Inhibiting 20s proteasome subunits β2 and β6 and β-transducin repeat-containing protein as antiviral therapies

Abstract

A method of treating a viral disease associated with targeting of PDZ domain proteins by a viral disease-inducing virus, in a subject in need of such therapy, comprising administering to the subject an inhibitor of at least one of 20s proteasome subunit β6 (Prosβ6), 20s proteasome subunit β2 (Prosβ2), and β-Transducin repeat-containing protein (βTrCP), thereby causing the death of cells that have been infected by the viral disease-inducing virus. The viral disease-inducing virus may be, for example, HPV, Adenovirus, Influenza A, HTLV-1, HIV, West Nile, Dengue, or SARS-CoV. Hie HPV may be a high-risk HPV strain such as HPV strain 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, or 68. The viral disease may be an HPV-induced cancer.

Description

Electronically Transmitted: September 24, 2025 OU 2024-004 PCT INHIBITING 20S PROTEASOME SUBUNITS β2 AND β6 AND β-TRANSDUCIN REPEAT-CONTAINING PROTEIN AS ANTIVIRAL THERAPIES STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0001] Not Applicable. CROSS REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent App. No. 63 / 698,116, filed on September 24, 2024. The entire contents of the above-referenced patent application(s) are hereby expressly incorporated herein by reference. REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

[0003] The instant application contains, as a separate part of the present disclosure, a Sequence Listing which has been submitted via EFS-Web in computer readable form as an XML file. The Sequence Listing, created September 23, 2025, is named “5863.114wo Sequence Listing.xml” and is 18,317 bytes in size. The entire contents of the Sequence Listing are hereby incorporated herein by reference. BACKGROUND

[0004] Many viruses including those with transforming and non-transforming activity such as HPV, Adenovirus, EBV, Influenza A, HTLV-1, HIV, West Nile, Dengue, and SARS-CoV target PDZ domain proteins of human cells. The common PDZ domain proteins targeted by these viruses are select proteins of cell-cell junction, cell polarity, and signal transduction pathways. Viral-mediated PDZ targeting results in functional perturbation of these proteins either through their inactivation or proteasome-mediated degradation. Given that a wide range of viruses have evolved mechanisms of PDZ targeting indicate that targeting PDZ proteins of host may be important for successful viral infection. In fact, several studies have demonstrated the involvement of PDZ targeting in viral replication, oncogenesis, cell immortalization, and dissemination in the host and to new hosts.

[0005] Human papillomaviruses (HPV) are small, double-stranded circular DNA viruses that are categorized into two classes: low-risk HPVs and high-risk HPVs. The former directs skin warts and are not cancerous. The latter are carcinogenic, causing almost all cervical cancers as well as strongly implicated in many head-neck, oropharyngeal, anal, vulvar, vaginal and penile cancers. Among all high-risk HPVs, HPV 16 and HPV 18 are the most prominent types, causing more than 70% of all invasive cervical cancers. According to World Health Organization (WHO), every year 660,000 women are diagnosed with cervical cancer with a current mortality rate of more than 50%. The availability of effective vaccines against the most prevalent high- risk HPVs is expected to eventually reduce HPV-dependent tumors. However, the number of new HPV-induced cancer cases is not predicted to appreciably decline for the next few decades. Economic and cultural barriers hinder widespread immunization in middle and low-income countries that account for the majority of cervical cancers. Further, chronic HPV infection can require several decades to provoke transformation.

[0006] HPV 16 and HPV 18 direct cellular transformation through the persistent expression of two viral early genes, E6 and E7. E6 and E7 oncoproteins cause cellular transformation through elimination of key tumor suppressors Rb and P53, respectively. High-risk HPV E6s contain a PDZ binding motif (PBM) at the extreme C terminus that is absent in low risk E6s. Interaction of the PBM with the PDZ domains of key host cellular PDZ domain proteins, including Magi, Dlg and Scribble, targets these proteins for ubiquitination and subsequent proteasome-mediated destruction. This action of E6 requires the assistance of the host E3 ubiquitin ligase, UBE3A and is necessary for cellular transformation. Transgenic mice deficient in the E6 PBM lack the ability to induce cellular transformation. The failure to induce cellular transformation is independent of P53, as PBM-deleted E6 retains the ability to inactivate P53. However, beyond the cellular targets of HPV oncogenes, we have a limited understanding of how persistent expression of E6 and E7 can lead to dysplasia and cancer.

[0007] Existing vaccines are only prophylactic against new HPV infections and are not effective against preexisting HPV infections, nor can they inhibit cancer progression and malignancy. Current treatments for invasive HPV-induced cancers are primarily radiation and chemotherapy, which show limited effectiveness. Furthermore, survival rates of patients with advanced-stage cervical cancer are low. As a result of these hurdles, effective treatments of HPV-induced cancers in general, including but not limited to HPV-induced cervical, head and neck, mouth, tongue, oropharyngeal, anal, vulvar, vaginal and penile cancers, remain a major unmet clinical need. It is to this unmet need that the present disclosure is directed.BRIEF DESCRIPTION OF THE DRAWINGS

[0008] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0009] FIG. 1 shows that blocking the function of 20s proteasome subunit β6, aka Prosβ6, (shown as Prosβ6 DN in the figures) or 20s proteasome subunit β2, aka Prosβ2, (shown as Prosβ2 DN in the figures) results in dramatic reduction of eyes expressing E6+hUBE3A (H compared to B). This result was specific to E6+hUBE3A as inhibition of those subunits individually or in combination did not affect wild type eyes (C, E, and G). The transgenes were expressed in the eyes using an eye-specific Gal4 driver, the GMR-Gal4. All eyes are from females and in the same magnification.

[0010] FIG.2 shows that blocking Prosβ6 or Prosβ2 results in apoptotic death of E6+hUBE3A- expressing eye tissue (D) indicated by Drosophila cleaved Dcp-1 (mammalian Cas3) staining. (A) WT eye tissue showing natural level of cell death. (B) E6+hUBE3A-expressing eye showing dramatic decrease in cell death. (C) Inhibition of Prosβ6 or Prosβ2 in WT eye does not affect cell death relative to control WT eye shown in A. All eyes are at the same stage and from females. (E) Inhibition of Prosβ6 and Prosβ2 blocks the E6-induced degradation of Magi. Graph shows quantification of three replicates normalized against Tubulin. * indicates a statistically significant change. p=0.022 (left), p=0.027 (right).

[0011] FIG.3 shows that anti-apoptotic function of E6 is mediated by proteasomal degradation of PDZ proteins. (A) control eye showing a ring of apoptotic cells to eliminate incomplete ommatidia from eye perimeter. (B) E6+hUBE3A expressing eye showing a significant reduction in apoptotic cell death. (C) Eye expressing a mutant E6 deficient in PDZ binding undergoes apoptosis.

[0012] FIG.4 shows co-inhibition of Prosβ6 and Prosβ2 in eyes expressing an intact E6 (D) or in eyes expressing an E6 deficient in PDZ binding, E6VA (E and F) results in more dramatic eye size reduction compared to condition in which the proteasome subunits are not inhibited in E6VA expressing cells (FIG.3C).

[0013] FIG. 5 shows that Prosβ6 and Prosβ2 co-inhibition enhances the PDZ-mediated apoptotic cell death. (A) wild type eye showing normal apoptotic cell death. (B) E6+hUBE3A expressing eye showing significant reduction in apoptotic cell death. (C) eye expressing hUBE3A plus a mutant E6 deficient in PDZ binding. PDZ binding deficiency of E6 impairs the anti-apoptotic function of E6 leading to apoptosis. (D) co-inhibition of Prosβ6 and Prosβ2 in eyes expressing E6VA enhances the E6VA-mediated cell death.

[0014] FIG. 6 shows that downregulation of slmb (human βTrCP) blocks anti-apoptotic function of E6 and enhances PDZ-mediated cell death. All transgenes are expressed using GMR-Gal4 that drives transgene expression in the entire eye. (A) control eye showing a ring of apoptotic cells. (B) E6+hUBE3A-expressing eye showing a dramatic reduction in cell death. (C) downregulation of slmb using RNAi has no effect on cell death when compared to control eye in A. (D) down regulation of slmb in the E6+hUBE3A-expressing eye interferes with anti- apoptotic activity of E6, inducing death. (E) E6 deficient in PDZ binding (E6VA) loses its ability to block cell death (E compared to B). (F) downregulation of slmb in eyes expressing E6VA dramatically enhances the E6VA-induced cell death. (G) inhibition of Prosβ6 interferes with anti-apoptotic function of E6. (H) co-inhibition of Prosβ6 and slmb induces apoptosis in a synergistic manner (compare H to G and D).

[0015] FIG.7 shows the effect of the reduction of the proteasome subunit β6 (PSMB1) by β6 siRNA 1 Duplex (SEQ ID NOS: 1-2) on the HPV-positive cervical cancer cell line SiHA. “+” indicates a positive control siRNA known to induce cell death. “–” indicates lipofectamine- treatment. Lipofectamine is the reagent used to deliverto the cells. p<0.05=*, p<0.01=**, p<0.001= *** and p<0.0001=****.

[0016] FIG.8 shows the effect of the reduction of the proteasome subunit β6 (PSMB1) by β6 siRNA 2 Duplex (SEQ ID NOS: 3-4) on the HPV-positive cervical cancer cell line SiHA. “+” indicates a positive control siRNA known to induce cell death. “–” indicates lipofectamine- treatment. Lipofectamine is the reagent used to deliver siRNAs to the cells. p<0.05=*, p<0.01=**, p<0.001= *** and p<0.0001=****.

[0017] FIG.9 shows the effect of the reduction of the proteasome subunit β2 (PSMB7) by β2 siRNA 1 Duplex (SEQ ID NOS: 5-6) on the HPV-positive cervical cancer cell line SiHA. “+” indicates a positive control siRNA known to induce cell death. “–” indicates lipofectamine- treatment. Lipofectamine is the reagent used to deliver siRNAs to the cells. p<0.05=*, p<0.01=**, p<0.001= *** and p<0.0001=****.

[0018] FIG.10 shows the effect of the reduction of the proteasome subunit β2 (PSMB7) by β2 siRNA 2 Duplex (SEQ ID NOS: 7-8) on the HPV-positive cervical cancer cell line SiHA. “+” indicates a positive control siRNA known to induce cell death. “–” indicatestreatment. Lipofectamine is the reagent used to deliverto the cells. p<0.05=*, p<0.01=**, p<0.001= *** and p<0.0001=****.

[0019] FIG.11 shows the effect of the reduction of the proteasome subunit β6 (PSMB1) by β6 siRNA 1 Duplex (SEQ ID NOS: 1-2) on the HPV-positive cervical cancer cell line CaSki. “+” indicates a positive control siRNA known to induce cell death. “–” indicates lipofectamine-treatment. Lipofectamine is the reagent used to deliver siRNAs to the cells. p<0.05=*, p<0.01=**, p<0.001= *** and p<0.0001=****.

[0020] FIG. 12 shows the effect of the reduction of the proteasome subunit β2 (PSMB7) by β2 siRNA 1 Duplex (SEQ ID NOS: 5-6) on the HPV-positive cervical cancer cell line CaSki. “+” indicates a positive control siRNA known to induce cell death. “–” indicates lipofectamine- treatment. Lipofectamine is the reagent used to deliver siRNAs to the cells. p<0.05=*, p<0.01=**, p<0.001= *** and p<0.0001=****.

[0021] FIG.13 shows the effect of the reduction of the proteasome subunit β6 (PSMB1) by β6 siRNA 1 Duplex (SEQ ID NOS: 1-2) on the noncancerous ectocervical cell line ECT1 / E6E7. “+” indicates a positive control siRNA known to induce cell death. “–” indicates lipofectamine- treatment. Lipofectamine is the reagent used to deliver siRNAs to the cells. p<0.05=*, p<0.01=**, p<0.001= *** and p<0.0001=****.

[0022] FIG.14 shows the effect of the reduction of the proteasome subunit β6 (PSMB1) by β6 siRNA 1 Duplex (SEQ ID NOS: 1-2) on the noncancerous endocervical cell line END1 / E6E7. “+” indicates a positive control siRNA known to induce cell death. “–” indicates lipofectamine- treatment. Lipofectamine is the reagent used to deliverto the cells. p<0.05=*, p<0.01=**, p<0.001= *** and p<0.0001=****.

[0023] FIG.15 shows the effect of the reduction of the proteasome subunit β2 (PSMB7) by β2 siRNA 1 Duplex (SEQ ID NOS: 5-6) on the noncancerous ectocervical cell line ECT1 / E6E7. “+” indicates a positive control siRNA known to induce cell death. “–” indicates lipofectamine- treatment. Lipofectamine is the reagent used to deliver siRNAs to the cells. p<0.05=*, p<0.01=**, p<0.001= *** and p<0.0001=****.

[0024] FIG.16 shows the effect of the reduction of the proteasome subunit β2 (PSMB7) by β2 siRNA 1 Duplex (SEQ ID NOS: 5-6) on the noncancerous endocervical cell line END1 / E6E7. “+” indicates a positive control siRNA known to induce cell death. “–” indicates lipofectamine- treatment. Lipofectamine is the reagent used to deliver siRNAs to the cells. p<0.05=*, p<0.01=**, p<0.001= *** and p<0.0001=****.

[0025] FIG. 17 shows reduction of β6 (PSMB1) as induced by β6 siRNA 1 Duplex (SEQ ID NOS: 1-2) in SiHa cell line and activation of apoptosis, represented by cleaved Poly (ADP- ribose) polymerase (PARP).

[0026] FIG. 18 shows reduction of β2 (PSMB7) as induced by β2 siRNA 1 Duplex (SEQ ID NOS: 5-6) and β2 siRNA 2 Duplex (SEQ ID NOS: 7-8) siRNA 2 in SiHa cell line and activation of apoptosis, represented by cleaved PARP.

[0027] FIG.19 shows the effect of the reduction of the proteasome subunit β6 (PSMB1) by β6 siRNA 1 Duplex (SEQ ID NOS: 1-2) on the HPV-positive oropharyngeal cancer cell line SCC2. “+” indicates a positive control siRNA known to induce cell death. “–” indicates lipofectamine-treatment. Lipofectamine is the reagent used to deliver siRNAs to the cells. p<0.05=*, p<0.01=**, p<0.001= *** and p<0.0001=****.

[0028] FIG.20 shows the effect of the reduction of the proteasome subunit β6 (PSMB1) by β6 siRNA 2 Duplex (SEQ ID NOS: 3-4) on the HPV-positive oropharyngeal cancer cell line SCC2. “+” indicates a positive control siRNA known to induce cell death. “–” indicates lipofectamine-treatment. Lipofectamine is the reagent used to deliver siRNAs to the cells. p<0.05=*, p<0.01=**, p<0.001= *** and p<0.0001=****.

[0029] FIG.21 shows the effect of the reduction of the proteasome subunit β6 (PSMB1) by β6 siRNA 1 Duplex (SEQ ID NOS: 1-2) an siRNA (siRNA 1) on the HPV-positive oropharyngeal cancer cell line SCC90. “+” indicates a positive control siRNA known to induce cell death. “– ” indicates lipofectamine-treatment. Lipofectamine is the reagent used to deliver siRNAs to the cells. p<0.05=*, p<0.01=**, p<0.001= *** and p<0.0001=****.

[0030] FIG.22 shows the effect of the reduction of the proteasome subunit β6 (PSMB1) by β6 siRNA 1 Duplex (SEQ ID NOS: 1-2) on the noncancerous endocervical cell line ECT1 / E6E7. ECT cells were used as control noncancerous cells due to their anatomical and histological similarity to oropharyngeal squamous cells and their relevance as a natural site of HPV infection. “+” indicates a positive control siRNA known to induce cell death. “–” indicates lipofectamine-treatment. Lipofectamine is the reagent used to deliver siRNAs to the cells. p<0.05=*, p<0.01=**, p<0.001= *** and p<0.0001=****.

[0031] FIG.23 shows the effect of the reduction of the proteasome subunit β2 (PSMB7) by β2 siRNA 1 Duplex (SEQ ID NOS: 5-6) on the HPV-positive oropharyngeal cancer cell line SCC2. “+” indicates a positive control siRNA known to induce cell death. “–” indicates lipofectamine-treatment. Lipofectamine is the reagent used to deliver siRNAs to the cells. p<0.05=*, p<0.01=**, p<0.001= *** and p<0.0001=****.

[0032] FIG.24 shows the effect of the reduction of the proteasome subunit β2 (PSMB7) by β2 siRNA 2 Duplex (SEQ ID NOS: 7-8) on the HPV-positive oropharyngeal cancer cell line SCC2. “+” indicates a positive control siRNA known to induce cell death. “–” indicates lipofectamine-treatment. Lipofectamine is the reagent used to deliverto the cells. p<0.05=*, p<0.01=**, p<0.001= *** and p<0.0001=****.

[0033] FIG.25 shows the effect of the reduction of the proteasome subunit β2 (PSMB7) by β2 siRNA 1 Duplex (SEQ ID NOS: 5-6) on the HPV-positive oropharyngeal cancer cell lineSCC90. “+” indicates a positive control siRNA known to induce cell death. “–” indicates lipofectamine-treatment. Lipofectamine is the reagent used to deliver siRNAs to the cells.p<0.05=*, p<0.01=**, p<0.001= *** and p<0.0001=****.

[0034] FIG.26 shows the effect of the reduction of the proteasome subunit β2 (PSMB7) by β2 siRNA 1 Duplex (SEQ ID NOS: 5-6) on the noncancerous endocervical cell line ECT1 / E6E7. ECT cells were used as control noncancerous cells due to their anatomical and histological similarity to oropharyngeal squamous cells and their relevance as a natural site of HPV infection. “+” indicates a positive control siRNA known to induce cell death. “–” indicates lipofectamine-treatment. Lipofectamine is the reagent used to deliver siRNAs to the cells. p<0.05=*, p<0.01=**, p<0.001= *** and p<0.0001=****.

[0035] FIG. 27 shows reduction of β6 (PSMB1) as induced by β6 siRNA 1 Duplex (SEQ ID NOS: 1-2) and β6 siRNA 2 Duplex (SEQ ID NOS: 3-4) in SCC-2 cell line and activation of apoptosis, represented by cleaved PARP.

[0036] FIG. 28 shows reduction of β2 (PSMB7) as induced by β2 siRNA 1 Duplex (SEQ ID NOS: 5-6) and β2 siRNA 2 Duplex (SEQ ID NOS: 7-8) in SCC-2 cell line and activation of apoptosis, represented by cleaved PARP.

[0037] FIG.29 shows results which assess the cytotoxicity effect of simultaneous reduction of proteasome subunits β6 (PSMB1)+β2 (PSMB7) in human cervical cells. Simultaneous siRNA- induced knockdown of β2 and β6 in HPV-positive SiHa cervical cancer cells results in greater cytotoxicity than the single siRNA treatments of β6 or β2. In contrast, simultaneous siRNA- induced knockdown of β2 and β6 has no effect on control noncancerous cells, ECT1 / E6E7 (see FIG.31). p<0.05=*, p<0.01=**, p<0.001= *** and p<0.0001=****.

[0038] FIG.30 shows results which assess the cytotoxicity effect of simultaneous reduction of proteasome subunits β6 (PSMB1)+β2 (PSMB7) in human head-neck cells. Simultaneous siRNA-induced knockdown of β2 and β6 in HPV-positive SCC2 oropharyngeal cancer cells results in greater cytotoxicity the single siRNA treatments of β6 or β2 by siRNAs. In contrast, simultaneous siRNA-induced knockdown of β2 and β6 has no effect on control noncancerous cells, ECT1 / E6E7 (see FIG.31). p<0.05=*, p<0.01=**, p<0.001= *** and p<0.0001=****.

[0039] FIG.31 shows control results which contrast with the cytotoxic effect of simultaneous reduction of proteasome subunits β6 (PSMB1)+β2 (PSMB7) in human cervical cells of FIG. 29 and human head-neck cells of FIG. 30. Simultaneous siRNA-induced knockdown of β2 and β6 has no effect on noncancerous control cells, ECT1 / E6E7. p<0.05=*, p<0.01=**, p<0.001= *** and p<0.0001=****.

[0040] FIG.32 shows the effect of the reduction of βTrCP by two siRNAs, βTrCP siRNA 1 Duplex (SEQ ID NOS: 9-10) and βTrCP siRNA 2 Duplex (SEQ ID NOS: 11-12), on the HPV- positive cervical cancer cell line SiHA. siRNA-induced reduction of βTrCP results in death of HPV-positive cervical cancer cells in the SiHa cell line. “+” indicates a positive control siRNA known to induce cell death. “–” indicates lipofectamine-treatment. Lipofectamine is the reagent used to deliver siRNAs to the cells. p<0.05=*, p<0.01=**, p<0.001= *** and p<0.0001=****.

[0041] FIG.33 shows the effect of the reduction of βTrCP by two siRNAs, βTrCP siRNA 1 Duplex (SEQ ID NOS: 9-10) and βTrCP siRNA 2 Duplex (SEQ ID NOS: 11-12), on the noncancerous cervical cell line END1 / E6E7. siRNA-induced reduction of βTrCP has no effect on noncancerous cervical cells in the END1 / E6E7 cell line. “+” indicates a positive control siRNA known to induce cell death. “–” indicates treatment. Lipofectamine is thereagent used to deliver siRNAs to the cells. p<0.05=*, p<0.01=**, p<0.001= *** and p<0.0001=****.

[0042] The following abbreviations are used herein:

[0043] βTrCP: β-Transducin repeat-containing protein,

[0044] Cas3: Caspase 3

[0045] COVID: Coronavirus disease,

[0046] COVID-19: Coronavirus disease-2019,

[0047] Dcp-1: Death Caspase-1,

[0048] Dlg: Drosophila discs large tumor suppressor,

[0049] DNA: Deoxyribonucleic Acid,

[0050] EBV: Epstein-Barr virus,

[0051] E6: HPV oncoprotein E6,

[0052] E6VA: E6 deficient in PDZ binding,

[0053] Gal4: Transcription factor Gal4,

[0054] GMR-Gal4: Glass multiple reporter-Gal4,

[0055] HIV: Human Immunodeficiency virus;

[0056] HPV: Human Papillomavirus,

[0057] HPVE6: Human Papillomavirus High risk E6 oncoprotein,

[0058] HPV16: Human Papillomavirus 16;

[0059] HPV18: Human Papillomavirus 18;

[0060] HTLV-1: Human T-cell lymphotrophic virus type 1,

[0061] hUBE3A: Human Ubiquitin ligase protein E3A,

[0062] Magi: Membrane-associate guanylate kinase,

[0063] PARP: Poly (ADP-ribose) polymerase,

[0064] PBM: PDZ binding motif,

[0065] PDZ: Postsynaptic density 95, Discs-large, and Zona occludens-1 protein,

[0066] Prosβ2: 20s proteasome subunit β2,

[0067] Prosβ2-DN: 20s proteasome subunit β2 (Prosβ2)-Dominant negative,

[0068] Prosβ6: 20s proteasome subunit β6,

[0069] Prosβ6-DN: 20s proteasome subunit β6 (Prosβ6)-Dominant negative,

[0070] PSMB1: proteasome 20s subunit beta-type 1, a.k.a. Prosβ6,

[0071] PSMB7: proteasome 20s subunit beta-type 7, a.k.a. Prosβ2,

[0072] RNA: Ribonucleic Acid,

[0073] SARS-CoV-2: Severe Acute Respiratory Syndrome-Coronavirus-2,

[0074] SCF: Skp1-Cullin 1-F-box protein complex,

[0075] SCFE3: SCF+E3 ubiquitin ligase complex,

[0076] Scribble: Scribble planar cell polarity protein,

[0077] siRNA: small interfering RNA,

[0078] Slmb: Human βTrCP,

[0079] UBE3A: Ubiquitin ligase protein E3A,

[0080] UPS: Ubiquitin-Proteasome System,

[0081] WT: wild type. DETAILED DESCRIPTION

[0082] The present disclosure, in at least certain embodiments, is directed to antiviral therapies for treating a subject for a viral disease associated with targeting of PDZ domain proteins or a Ubiquitin-Proteasome System (UPS) by a viral disease-inducing virus. The therapy can be administering to the subject an inhibitor of at least one of 20s proteasome subunit β6 (Prosβ6), 20s proteasome subunit β2 (Prosβ2), and β-Transducin repeat-containing protein (βTrCP), thereby causing the death of cells that have been infected by the viral disease-inducing virus. The viral disease-inducing virus may be, for example, a Human Papillomavirus (HPV), Adenovirus, Influenza A, HTLV-1, HIV, West Nile, Dengue, and SARS-CoV. The infected cells may be HPV oncogene E6-expressing cells. Inhibition of either Prosβ6 (a.k.a., Prosβ6-DN) or Prosβ2 (a.k.a., Prosβ2-DN) blocks degradation of PDZ domain proteins, thereby leading to cell death. Since many viruses utilize the PDZ binding motif (PBM)-PDZ interaction mechanism for their pathogenesis in humans, the blocking of the Prosβ6 or Prosβ2 and thus the resultinginterference with the viral-mediated PBM-PDZ interactions, inhibitors of Prosβ6 and / or Prosβ2 can be used in novel anti-viral therapeutic treatments.

[0083] This lab developed the first Drosophila models of the two most prevalent high-risk types of HPV oncogene-mediated pathogenesis (HPV18 and HPV16) and have been utilizing these models for understanding the action of viral oncoproteins. The HPV oncoprotein E6 possesses a PBM at its C terminus, which interacts with select PDZ domain proteins such as Magi, Dlg, and Scribble. Proteasome-mediated degradation is the endpoint for most E6- interacting host cellular proteins. This is due to E6 ability to recruit cellular E3 ubiquitin ligase (UBE3A) for ubiquitination of its PDZ target proteins, whereby the ubiquitinylated PDZ proteins are directed for degradation. The lab has recently discovered that inhibition of Prosβ6 and Prosβ2, two highly conserved beta subunits of proteasome 20s, restores the expression of PDZ domain protein Magi and induces cell death in Drosophila tissues expressing E6+hUBE3A. This effect was specific to E6+hUBE3A-expressing tissue, as no effects were observed when these subunits were inhibited in WT tissue. Additionally, it’s shown that cell death induced by proteasome inhibition is partly due to restoration of PDZ proteins as E6 deficient in PDZ binding fails to block cell death. Searching for candidate targets which can work synergistically with PDZ-mediated cell death led to identification of Drosophila Slmb (Human βTrCP), an F-box protein of SCF (Skp1-Cullin 1-F-box protein) E3 ubiquitin ligase whose inhibition dramatically enhanced PDZ-mediated cell death. It is believed that Prosβ2 inhibition, Prosβ6 inhibition, co-inhibition of Prosβ6 and Prosβ2, or co-inhibition of Prosβ6 / Prosβ2 / βTrCP have not been previously investigated for development of HPV-induced cancer therapies. Hence Prosβ6, Prosβ2, and βTrCP were perceived herein as targets worth investigating for development of molecularly-targeted therapeutics, used either alone (Prosβ6, or Prosβ2, or βTrCP), or in combination (e.g., Prosβ6+Prosβ2, Prosβ6+βTrCP, Prosβ2+βTrCP, or Prosβ6+Prosβ2+βTrCP).

[0084] Before further describing various embodiments of the compositions, kits, and methods of the present disclosure in more detail by way of exemplary description, examples, and results, it is to be understood that the present disclosure is not limited in application to the details of methods and compositions as set forth in the following description. The description provided herein is intended for purposes of illustration only and is not intended to be construed in a limiting sense. The inventive concepts of the present disclosure are capable of other embodiments or of being practiced or carried out in various ways. As such, the language used herein is intended to be given the broadest possible scope and meaning; and the embodiments are meant to be exemplary, not exhaustive. Also, it is to be understood that the phraseology andterminology employed herein is for the purpose of description and should not be regarded as limiting unless otherwise indicated as so. Moreover, in the following detailed description, numerous specific details are set forth in order to provide a more thorough understanding of the disclosure. However, it will be apparent to a person having ordinary skill in the art that the present disclosure may be practiced without these specific details. In other instances, features which are well known to persons of ordinary skill in the art have not been described in detail to avoid unnecessary complication of the description. It is intended that all alternatives, substitutions, modifications, and equivalents apparent to those having ordinary skill in the art are included within the scope of the present disclosure as defined herein. Thus, while the compositions and methods of the present disclosure have been described in terms of particular embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and / or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit, and scope of the inventive concepts.

[0085] All patents, published patent applications, and non-patent publications mentioned in the specification are indicative of the level of skill of those skilled in the art to which the present disclosure pertains. All patents, published patent applications, and non-patent publications referenced in any portion of this application, including U.S. Prov. Patent App. No.63 / 698,116 filed on September 24, 2024, are herein expressly incorporated by reference in their entirety to the same extent as if each individual patent or publication was specifically and individually indicated to be incorporated by reference.

[0086] Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those having ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Where used herein, the specific term “single” is limited to only “one.”

[0087] Where used herein, the pronouns “we” or “us” or the possessive determiner “our” are intended to refer to all persons involved in a particular aspect of the investigation disclosed herein and as such may include non-inventor laboratory personnel, assistants, technicians, collaborators and / or contributors who worked under the supervision of the inventor(s), and thus are not intended to represent an inventorship role by said laboratory personnel, assistants, technicians, collaborators, and / or contributors in any subject matter disclosed herein.

[0088] The term “high-risk strain” where used herein in association with HPV, refers to strains of HPV which have an enhanced potential to cause cancer, and include, but are not limited to, HPV strains 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68.

[0089] The term “duplex,” where used herein in association with the term “siRNA,” refers to a pair of RNA sequences (a guide strand and a passenger strand) which function in concert to cause the interfering effect of the siRNA.

[0090] As utilized in accordance with the methods, compounds, and compositions of the present disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings.

[0091] The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and / or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” The use of the term “or” in the claims is used to mean “and / or” unless explicitly indicated to refer to alternatives only or when the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and / or.” The use of the term “at least one” will be understood to include one as well as any quantity more than one, including but not limited to, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 100, or any integer inclusive therein. The term “at least one” may extend up to 100 or 1000 or more, depending on the term to which it is attached; in addition, the quantities of 100 / 1000 are not to be considered limiting, as higher limits may also produce satisfactory results. In addition, the use of the term “at least one of X, Y, and Z” will be understood to include X alone, Y alone, and Z alone, as well as any combination of X, Y, and Z.

[0092] As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. Use of the word “we” as a pronoun herein refers generally to laboratory personnel or other contributors who assisted in laboratory procedures and data collection and is not intended to represent an inventorship role by said laboratory personnel or other contributors in any subject matter disclosed herein.

[0093] The term “or combinations thereof” as used herein refers to all permutations and combinations of the listed items preceding the term. For example, “A, B, C, or combinations thereof” is intended to include at least one of: A, B, C, AB, AC, BC, or ABC, and if order isimportant in a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing with this example, expressly included are combinations that contain repeats of one or more item or term, such as BB, AAA, AAB, BBC, AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan will understand that typically there is no limit on the number of items or terms in any combination, unless otherwise apparent from the context.

[0094] As used herein, all numerical values or ranges include fractions of the values and integers within such ranges and fractions of the integers within such ranges unless the context clearly indicates otherwise. Thus, to illustrate, reference to a numerical range, such as 1-10 includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, as well as 1.1, 1.2, 1.3, 1.4, 1.5, etc., and so forth. Reference to a range of 1-50 therefore includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc., up to and including 50, as well as 1.1, 1.2, 1.3, 1.4, 1.5, etc., 2.1, 2.2, 2.3, 2.4, 2.5, etc., and so forth. Reference to a series of ranges includes ranges which combine the values of the boundaries of different ranges within the series. Thus, to illustrate reference to a series of ranges, for example, of 1-10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-75, 75-100, 100-150, 150- 200, 200-250, 250-300, 300-400, 400-500, 500-750, 750-1,000, includes ranges of 1-20, 10- 50, 50-100, 100-500, and 500-1,000, for example.

[0095] As noted above, any numerical range listed or described herein is intended to include, implicitly or explicitly, any number or sub-range within the range, particularly all integers, including the end points, and is to be considered as having been so stated. For example, "a range from 1.0 to 10.0" is to be read as indicating each possible number, including integers and fractions, along the continuum between and including 1.0 and 10.0, that is, having a minimum value equal to or greater than 1.0 and a maximum value equal to or less than 10.0, such as, for example, 3.25 to 8.65. Any maximum numerical limitation recited herein is intended to include all lower numerical limitations subsumed therein, and any minimum numerical limitation recited in this specification is intended to include all higher numerical limitations subsumed therein. Accordingly, Applicant reserves the right to amend this specification, including the claims, to expressly recite any sub-range subsumed within the ranges expressly recited herein. Thus, even if a particular data point within the range is not explicitly identified or specifically referred to, it is to be understood that any data points within the range are to be considered to have been specified, and that the inventor(s) possessed knowledge of the entire range and the points within the range.

[0096] Throughout this application, the terms “about” or “approximately” are used to indicate that a value includes the inherent variation of error for the composition, the method used to administer the composition, or the variation that exists among the study subjects. As usedherein the qualifiers “about” or “approximately” are intended to include not only the exact value, amount, degree, orientation, or other qualified characteristic or value, but are intended to include some slight variations due to measuring error, manufacturing tolerances, stress exerted on various parts or components, observer error, wear and tear, and combinations thereof, for example. The term “about” or “approximately,” where used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass, for example, variations of ± 20% or ± 10%, or ± 5%, or ± 1%, or ± 0.1% from the specified value, as such variations are appropriate to perform the disclosed methods and as understood by persons having ordinary skill in the art.

[0097] As used herein, the term “substantially” means that the subsequently described event or circumstance completely occurs or that the subsequently described event or circumstance occurs to a great extent or degree. For example, the term “substantially” means that the subsequently described event or circumstance occurs at least 90% of the time, or at least 95% of the time, or at least 98% of the time.

[0098] The terms “significant” and “significantly” when used non-statistically in reference to a quantitative reference measure, are defined as meaning at least 5% of a reference measure, or at least 10% of a reference measure, or at least 20% of a reference measure, or at least 30% of a reference measure, or at least 40% of a reference measure, or at least 50% of a reference measure, or at least 60% of a reference measure, or at least 70% of a reference measure, or at least 80% of a reference measure, or at least 90% of a reference measure, or at least 95% of a reference measure, including 100% of a reference measure.

[0099] As used herein any reference to "one embodiment" or "an embodiment" means that a particular element, feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment and may be included in other embodiments. The appearances of the phrase "in one embodiment" in various places in the specification are not necessarily all referring to the same embodiment and are not necessarily limited to a single or particular embodiment.

[0100] The term “active agent” refers to a compound which has a biologic activity as described herein, such as a treatment and / or diagnostic modality which has a therapeutic and / or diagnostic benefit in accordance with the present disclosure. By “biologically active” is meant the ability of an agent to modify the physiological system of an organism without reference to how the agent (“active agent”) has its physiological effects.

[0101] The term “theranostic” refers to an active agent which has both a therapeutic and a diagnostic activity in accordance with the present disclosure.

[0102] When two or more active agents described in present disclosure, or their equivalents, are administered, they may be used or administered conjointly. As used herein the terms “conjointly” or “conjoint administration” refers to any form of administration of two or more different biologically-active compounds (i.e., active agents) such that the second compound is administered while the previously administered therapeutic compound is still effective in the body, whereby the two or more compounds are simultaneously active in the patient. For example, the different therapeutic compounds can be administered either in the same formulation, or in separate formulations, either concomitantly (together) or sequentially. When administered sequentially the different compounds may be administered immediately in succession, or separated by a suitable duration of time, as long as the active agents function together in a synergistic manner. In certain embodiments, the different therapeutic compounds can be administered within one hour of each other, within two hours of each other, within 3 hours of each other, within 6 hours of each other, within 12 hours of each other, within 24 hours of each other, within 36 hours of each other, within 48 hours of each other, within 72 hours of each other, or more. Thus an individual who receives such treatment can benefit from a combined effect of the different therapeutic compounds.

[0103] The term “pharmaceutically acceptable” refers to compounds and compositions which are suitable for administration to humans and / or animals without undue adverse side effects such as toxicity, irritation and / or allergic response commensurate with a reasonable benefit / risk ratio.

[0104] As used herein, “pure” or “substantially pure” means an object species is the predominant species present (i.e., on a molar basis it is more abundant than any other object species in the composition thereof), and particularly a substantially purified fraction is a composition wherein the object species comprises at least about 50 percent (on a molar basis) of all macromolecular species present. Generally, a substantially pure composition will comprise more than about 80% of all macromolecular species present in the composition, more particularly more than about 85%, more than about 90%, more than about 95%, or more than about 99%. The term “pure” or “substantially pure” also refers to preparations where the object species (e.g., the peptide compound) is at least 60% (w / w) pure, or at least 70% (w / w) pure, or at least 75% (w / w) pure, or at least 80% (w / w) pure, or at least 85% (w / w) pure, or at least 90% (w / w) pure, or at least 92% (w / w) pure, or at least 95% (w / w) pure, or at least 96% (w / w) pure,or at least 97% (w / w) pure, or at least 98% (w / w) pure, or at least 99% (w / w) pure, or 100% (w / w) pure.

[0105] The terms “subject” and “patient” are used interchangeably herein and will be understood to refer to a warm-blooded animal, particularly a mammal, and more particularly, humans. Animals which fall within the scope of the term “subject” as used herein include, but are not limited to, dogs, cats, rats, mice, guinea pigs, chinchillas, horses, goats, ruminants such as cattle, sheep, swine, camelids such as llamas, alpacas, guanacos, and vicunas, poultry such as chickens, geese, ducks, and turkeys, zoo animals, Old and New World monkeys, and non- human primates.

[0106] “Treatment” refers to therapeutic treatments, such as for promoting wound healing. “Prevention” refers to prophylactic or preventative treatment measures. The term “treating” refers to administering the composition to a patient for therapeutic purposes such as for promoting wound healing.

[0107] The terms “therapeutic composition” and “pharmaceutical composition” refer to an active agent-containing composition that may be administered to a subject by any method known in the art or otherwise contemplated herein, wherein administration of the composition brings about a therapeutic effect as described elsewhere herein. In addition, the compositions of the present disclosure may be designed to provide delayed, controlled, extended, and / or sustained release using formulation techniques which are well known in the art.

[0108] The term “effective amount” refers to an amount of an active agent (e.g., a Prosβ6, Prosβ2, or βTrCP inhibitor) which is sufficient to exhibit a detectable therapeutic effect without excessive adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit / risk ratio when used in the manner of the inventive concepts. The therapeutic effect may include, for example but not by way of limitation, a partial or complete elimination of an HPV-induced cancer. The effective amount for a patient will depend upon the type of patient, the patient’s size and health, the nature and severity of the condition to be treated, the method of administration, the duration of treatment, the nature of concurrent therapy (if any), the specific formulations employed, and the like. The effective amount for a given situation can be determined by one of ordinary skill in the art based on the information provided herein.

[0109] The term "ameliorate" means a detectable or measurable improvement in a subject's condition, disease, or symptom thereof. A detectable or measurable improvement includes a subjective or objective decrease, reduction, inhibition, closure, suppression, limit, or control in the occurrence, frequency, severity, progression, or duration of the condition or disease, or animprovement in a symptom or an underlying cause or a consequence of the disease, or a reversal of the disease. A successful treatment outcome can lead to a "therapeutic effect" or "benefit" of completely or partially decreasing, reducing, inhibiting, suppressing, limiting, controlling, or preventing the occurrence, frequency, severity, progression, or duration of a disease or condition, or consequences of the disease or condition.

[0110] A decrease or reduction in the worsening of a disease or condition, such as stabilizing the condition or disease, such as a tumor, is also a successful treatment outcome. A therapeutic benefit therefore need not be complete ablation or reversal of the disease or condition, or of any one of, or most, or all adverse symptoms, complications, consequences, or underlying causes associated with the disease or condition. Thus, a satisfactory endpoint may be achieved when there is an incremental improvement such as a partial decrease, reduction, inhibition, suppression, limit, control, or prevention in the occurrence, frequency, severity, progression, or duration, or inhibition or reversal of the condition or disease (e.g., stabilizing), over a short or long duration of time (hours, days, weeks, months, etc.), such as partial closure of a wound. Effectiveness of a method or use, such as a treatment that provides a potential therapeutic benefit or improvement of a condition or disease, can be ascertained by various methods, measurements, and testing assays.

[0111] In certain non-limiting embodiments, the dosage of the Prosβ6, Prosβ2, or βTrCP inhibitor administered to a subject could be in a range of about 1 μg per kg of subject body mass to about 1000 mg / kg, or in a range of about 5 μg / kg to about 500 mg / kg, or in a range of about 10 μg / kg to about 300 mg / kg, or in a range of about 25 μg / kg to about 250 mg / kg, or in a range of about 50 μg / kg to about 250 mg / kg, or in a range of about 75 μg / kg to about 250 mg / kg, or in a range of about 100 μg / kg to about 250 mg / kg, or in a range of about 200 μg / kg to about 250 mg / kg, or in a range of about 300 μg / kg to about 250 mg / kg, or in a range of about 400 μg / kg to about 250 mg / kg, or in a range of about 500 μg / kg to about 250 mg / kg, or in a range of about 600 μg / kg to about 250 mg / kg, or in a range of about 700 μg / kg to about 250 mg / kg, or in a range of about 800 μg / kg to about 250 mg / kg, or in a range of about 900 μg / kg to about 250 mg / kg, or in a range of about 1 mg / kg to about 200 mg / kg, or in a range of about 1 mg / kg to about 150 mg / kg, or in a range of about 2 mg / kg to about 100 mg / kg, or in a range of about 5 mg / kg to about 100 mg / kg, or in a range of about 10 mg / kg to about 100 mg / kg, or in a range of about 25 mg per kg to about 75 mg / kg.

[0112] The one or more Prosβ6, Prosβ2, or βTrCP inhibitors (used alone or in combination) can be administered, for example but not by way of limitation, on a one-time basis, or administered at multiple times (for example but not by way of limitation, from one to five timesper day, or once or twice per week), or continuously via a venous drip, depending on the desired therapeutic effect. In one non-limiting example of a therapeutic method of the present disclosure, the composition is provided in an IV infusion. Administration of the compounds used in the pharmaceutical composition or to practice the method of the present disclosure can be carried out in a variety of conventional ways, such as, but not limited to, topically, orally, by inhalation (e.g., intrabronchial, intranasal or oral inhalation, intranasal drops), rectally, or by cutaneous, subcutaneous, intraperitoneal, or parenteral (e.g., intravenous, intraarterial, intramuscular, subcutaneous injection) injection. Oral formulations may be formulated such that the compounds pass through a portion of the digestive system before being released, for example it may not be released until reaching the small intestine, or the colon. When the active agent is delivered by inhalation, it may be delivered via a soft mist nebulizer (e.g., a jet, ultrasonic, or vibrating-mesh nebulizer), a pressurized metered-dose inhaler (MDI), or a dry powder inhaler (DPI), or by any other suitable means, e.g., via a catheter inserted directly into the lung, or via a ventilator when a patient himself or herself is unable to inhale voluntarily.

[0113] In certain embodiments, the methods of the present disclosure include topical, transdermal, sub-dermal, enteral, parental or intravenous administration of an active agent (one or more Prosβ6, Prosβ2, or βTrCP inhibitors). For example (but not by way of limitation), topical administration of the active agent may comprise the administration of a cream, gel, ointment, spray, lip-balm, balm, emulsion, liposome, liquid crystal preparation or lotion, or any combination thereof. In one embodiment, administration comprises an at least once a day administration for one or more days (e.g., about 1 to about 30 days) until at least one symptom of the inflammatory disease or condition is alleviated. In another embodiment, administration comprises an at least twice a day administration for one or more days (e.g., about 1 to about 30 days) until at least one symptom of the condition is alleviated. In another embodiment, administration comprises an at least about 3 to about 6 times per day administration for one or more days (e.g., about 1 to about 30 days) until at least one symptom of the condition is alleviated.

[0114] The composition for topical or internal application may be provided in any suitable solid, semi-solid, or liquid form. In certain embodiments, the topical composition may be provided in or be disposed in a carrier(s) or vehicle(s) such as, for example (but not by way of limitation), creams, pastes, gums, lotions, gels, foams, ointments, emulsions, suspensions, aqueous solutions, powders, lyophilized powders, solutions, granules, foams, drops, eye drops, adhesives, sutures, aerosols, sprays, sticks, soaps, bars of soap, balms, body washes, rinses, tinctures, gel beads, gauzes, wound dressings, bandages, cloths, towelettes, stents, and sponges.Non-limiting examples of formulations of such carriers and vehicles include, but are not limited to, those shown in “Remington, The Science and Practice of Pharmacy,” 22nd ed., 2012, edited by Loyd V. Allen, Jr.

[0115] Creams are emulsions of water in oil (w / o), or oil in water (o / w). O / w creams spread easily and do not leave the skin greasy and sticky. W / o creams tend to be more greasy and more emollient. Ointments are semi-solid preparations of hydrocarbons and the strong emollient effect makes it useful in cases of dry skin. The occlusive effect enhances penetration of the active agent and improves efficacy. Pastes are mixtures of powder and ointment. The addition of the powder improves porosity thus breathability. The addition of the powder to the ointment also increases consistency so the preparation is more difficult to rub off or contact non-affected areas of the skin. Lotions are liquid preparations in which inert or active medications are suspended or dissolved. For example, an o / w emulsion with a high water content gives the preparation a liquid consistency of a lotion. Most lotions are aqueous of hydroalcoholic systems wherein small amounts of alcohol are added to aid in solubilization of the active agent and to hasten evaporation of the solvent from the skin surface. Gels are transparent preparations containing cellulose ethers or carbomer in water, or a water-alcohol mixture. Gels liquefy on contact with the skin, dry, and leave a thin film of active medication.

[0116] In certain non-limiting embodiments, the composition may comprise the active agents in a concentration of, but is not limited to, about 0.0001 M to about 1 M, for example, or about 0.001 M to about 0.1 M. The composition may comprise about 0.01 to about 1000 milligrams of the active agents per ml of carrier or vehicle with which the active agents are combined in a composition or mixture. The composition may comprise about 1 wt% to about 90 wt% (or about 1 mass% to about 90 mass%) of one or more shikimate analogues and about 10 wt% to about 99 wt% (or about 10 mass% to about 99 mass%) of one or more secondary compounds (where “wt%” is defined as the percentage by weight of a particular compound in a solid or liquid composition, and “mass%” is defined as the percentage by mass of a particular compound in a solid or liquid composition).

[0117] The topical compositions may further comprise ingredients such as (but not limited to) propylene glycol, sodium stearate, glycerin, a surfactant (e.g., sodium laurate, sodium laureth sulfate, and / or sodium lauryl sulfate), and water, and optionally, sorbitol, sodium chloride, stearic acid, lauric acid, aloe vera leaf extract, pentasodium penetrate, and / or tetrasodium etidronate.

[0118] The topical compositions may be formulated with liquid or solid emollients, solvents, thickeners, or humectants. Emollients include, but are not limited to, stearyl alcohol, mink oil,cetyl alcohol, oleyl alcohol, isopropyl laurate, polyethylene glycol, olive oil, petroleum jelly, palmitic acid, oleic acid, and myristyl myristate. Emollients may also include natural butters extracted from various plants, trees, roots, or seeds. Examples of such butters include, but are not limited to, shea butter, cocoa butter, avocado butter, aloe butter, coffee butter, mango butter, or combination thereof.

[0119] Suitable materials which may be used in the compositions as carriers or vehicles or secondary compounds or solvents include, but are not limited to, propylene glycol, ethyl alcohol, isopropanol, acetone, diethylene glycol, ethylene glycol, dimethyl sulfoxide, and dimethyl formamide. Suitable humectants include, but are not limited to, acetyl arginine, algae extract, Aloe barbadensis leaf extract, 2,3-butanediol, chitosan lauroyl glycinate, diglycereth-7 malate, diglycerin, diglycol guanidine succinate, erythritol, fructose, glucose, glycerin, honey, hydrolyzed wheat protein / polyethylene glycol-20 acetate copolymer, hydroxypropyltrimonium hyaluronate, inositol, lactitol, maltitol, maltose, mannitol, mannose, methoxypolyethylene glycol, myristamidobutyl guanidine acetate, polyglyceryl sorbitol, potassium pyrollidone carboxylic acid (PCA), propylene glycol (PGA), sodium pyrollidone carboxylic acid (PCA), sorbitol, and sucrose. Other humectants may be used for yet additional embodiments of the compositions of the present disclosure.

[0120] Suitable thickeners include, but are not limited to, polysaccharides, in particular xantham gum, guar-guar, agar-agar, alginates, carboxymethylcellulose, relatively high molecular weight polyethylene glycol mono- and diesters of fatty acids, polyacrylates, polyvinyl alcohol and polyvinylpyrrolidone, surfactants such as, for example, ethoxylated fatty acid glycerides, esters of fatty acids with polyols such as, for example, pentaerythritol or trimethylpropane, fatty alcohol ethoxylates or alkyl oligoglucosides, and electrolytes, such as sodium chloride and ammonium chloride.

[0121] The topical compositions may further comprise one or more penetrants, compounds facilitating penetration of active ingredients into the skin of a patient. Non-limiting examples of suitable penetrants include isopropanol, polyoxyethylene ethers, terpenes, cis-fatty acids (oleic acid, palmitoleic acid), acetone, laurocapram dimethyl sulfoxide, 2-pyrrolidone, oleyl alcohol, glyceryl-3-stearate, cholesterol, myristic acid isopropyl ester, and propylene glycol. Additionally, the compositions may include surfactants or emulsifiers for forming emulsions. Either a water-in-oil or oil-in-water emulsion may be formulated. Examples of suitable emulsifiers include, but are not limited to, stearic acid, cetyl alcohol, PEG-100, stearate and glyceryl stearate, cetearyl glucoside, polysorbate 20, methylcellulose, sodium carboxymethylcellulose, glycerin, bentonite, ceteareth-20, cetyl alcohol, cetearyl alcohol,lanolin alcohol, riconyl alcohol, self-emulsifying wax (e.g., Lipowax P), cetyl palmitate, stearyl alcohol, lecithin, hydrogenated lecithin, steareth-2, steareth-20, and polyglyceryl-2 stearate.

[0122] When a therapeutically effective amount of the composition(s) is administered orally, it may be in the form of a solid or liquid preparation such as (but not by way of limitation) capsules, pills, tablets, lozenges, melts, powders, suspensions, solutions, elixirs or emulsions. Solid unit dosage forms can be capsules of the ordinary gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, and cornstarch, or the dosage forms can be sustained release preparations. The pharmaceutical composition(s) may contain a solid carrier, such as a gelatin or an adjuvant. The tablet, capsule, and powder may contain from about .05 to about 95% of the active agent by dry weight. When administered in liquid form, a liquid carrier such as (but not limited to) water, petroleum, oils of animal or plant origin such as peanut oil, mineral oil, soybean oil, or sesame oil, or synthetic oils may be added. The liquid form of the pharmaceutical composition(s) may further contain physiological saline solution, dextrose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol, or polyethylene glycol. When administered in liquid form, the pharmaceutical composition(s) particularly contains from about 0.005% to about 95% by weight of the active substance. For example (but not by way of limitation), a dose of about 10 mg to about 1000 mg once or twice a day could be administered orally.

[0123] In another non-limiting embodiment, the composition(s) of the present disclosure can be tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders, such as acacia, cornstarch, or gelatin, disintegrating agents such as potato starch or alginic acid, and a lubricant such as stearic acid or magnesium stearate. Liquid preparations are prepared by dissolving the composition(s) in an aqueous or non-aqueous pharmaceutically acceptable solvent which may also contain suspending agents, sweetening agents, flavoring agents, and preservative agents as are known in the art.

[0124] For parenteral administration, for example, the composition(s) may be dissolved in a physiologically acceptable pharmaceutical carrier and administered as either a solution or a suspension. Illustrative of suitable (but non-limiting) pharmaceutical carriers are water, saline, dextrose solutions, fructose solutions, ethanol, or oils of animal, vegetative, or synthetic origin. The pharmaceutical carrier may also contain preservatives and buffers as are known in the art.

[0125] When a therapeutically effective amount of the composition(s) is administered by intravenous, cutaneous, or subcutaneous injection, the active agent may be in the form of a pyrogen-free, parenterally acceptable aqueous solution or suspension. The preparation of such parenterally acceptable solutions, having due regard to pH, isotonicity, stability, and the like,is well within the skill in the art. A particular pharmaceutical composition for intravenous, cutaneous, or subcutaneous injection may contain, in addition to the active agent(s), an isotonic vehicle such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, Lactated Ringer's Injection, or other vehicle as known in the art. The pharmaceutical composition(s) of the present disclosure may also contain stabilizers, preservatives, buffers, antioxidants, or other additives known to those of skill in the art.

[0126] Additional pharmaceutical methods may be employed to control the duration of action of the composition(s). Increased half-life and / or controlled release preparations may be achieved through the use of polymers to conjugate, complex with, and / or absorb the active substances described herein. The controlled delivery and / or increased half-life may be achieved by selecting appropriate macromolecules (for example but not by way of limitation, polysaccharides, polyesters, polyamino acids, homopolymers polyvinyl pyrrolidone, ethylenevinylacetate, methylcellulose, or carboxymethylcellulose, and acrylamides such as N-(2-hydroxypropyl) methacrylamide), and the appropriate concentration of macromolecules as well as the methods of incorporation, in order to control release. The active agent(s) may also be ionically or covalently conjugated to the macromolecules described above, as long as they retain activity. Another possible method useful in controlling the duration of action of the composition(s) by controlled release preparations and half-life is incorporation of the composition(s) or functional derivatives thereof into particles of a polymeric material such as (but not limited to) polyesters, polyamides, polyamino acids, hydrogels, poly(lactic acid), ethylene vinylacetate copolymers, copolymer micelles of, for example, PEG and poly(l- aspartamide).

[0127] In at least one embodiment, the present disclosure is directed to a method of inhibiting growth of human papillomavirus (HPV)-induced cancer cells, in vivo or in vitro, by exposing the cells to an inhibitor of Prosβ6, or Prosβ2, or βTrCP (individually or in combination). In at least one embodiment, the present disclosure is directed to a method of treating a human papillomavirus (HPV)-induced cancer in a subject by administering to the subject an effective amount of an inhibitor of Prosβ6, or Prosβ2, or βTrCP (individually or in combination). The HPV-induced cancers which may be treated using the presently disclosed methods include, but are not limited to, cervical, head and neck, mouth, tongue, oropharyngeal, anal, vulvar, vaginal and penile cancers. Inhibitors that may be used in the present disclosure include but are not limited to LU-102, LU-002c, MG-132, Bortezomib, Carfilzomib, Ixazomib, Marizomib, Oprozomib, Delanzomib, Acyclovir, Erioflorin, GS143, and PHAR. The cancers may be of any grade, and may be resistant to current therapies. In the event the cancer becomes resistant toone of the disclosed inhibitors, treatment can be switched to another of the inhibitors contemplated herein.

[0128] Certain novel embodiments of the present disclosure, having now been generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present disclosure, and are not intended to be limiting. The following detailed examples are to be construed, as noted above, only as illustrative, and not as limiting of the present disclosure in any way whatsoever. Those skilled in the art will promptly recognize appropriate variations from the various compositions, structures, components, procedures and methods.

[0129] Methods and Results

[0130] Using a Drosophila model of HPVE6+hUBE3A-induced pathogenesis, it was discovered that functional inhibition of Prosβ6 or Prosβ2 using dominant negative transgenes in HPVE6+hUBE3A expressing eyes results in eye size reduction (FIG. 1(D, F) compared to FIG.1(B). This effect was exacerbated when both subunits were blocked simultaneously (FIG. 1(H) compared to FIG.(D, F)). The lab also found that the effect was specific to E6+hUBE3A- expressing eye, as no defects were observed when these subunits were inhibited in wild type eyes (FIG.1(C, E,G)).

[0131] Next investigated was whether the eye size reduction was due to a cytotoxicity effect of proteasome inhibition on E6+hUBE3A-expressing cells. Immunofluorescence analysis for apoptotic cell death marker, Dcp-1, revealed that inhibition of Prosβ6 and Prosβ2 induces apoptotic cell death of E6+hUBE3A expressing tissues (FIG. 2(D) compared to FIG. 2(B)). Results demonstrated that inhibition of these two proteasomal subunits blocks E6-induced proteasomal degradation of PDZ protein Magi (FIG.2(E)). This cytotoxicity effect was specific to E6+hUBE3A-expressing eye tissue, as no effects were observed when these subunits were inhibited in wild type eye tissue (FIG.2(C)). These results suggested that apoptotic cell death induced by proteasome inhibition could in part be due to restoration of PDZ domain proteins as their degradation is shown to be essential for HPV-induced cancer. Hence, a mutant form of E6 deficient in interacting with PDZ domain proteins was expressed and was found to have lost its ability to block cell death (FIG.3(C) compared to FIG.3(B)).

[0132] The results further demonstrated that Prosβ6 and Prosβ2 co-inhibition not only activates PDZ-mediated apoptosis but also induces PDZ-independent apoptotic cell death mechanisms. This is evident by the severity of eye degeneration when these subunits are co-inhibited in tissues expressing either an intact E6 or an E6 deficient in PDZ binding (FIG.4(D-F) comparedto FIG. 4(C)). Further examination of their eyes for apoptotic cell death revealed that co- inhibition of Prosβ6 and Prosβ2 subunits enhances the PDZ-mediated apoptotic cell death (FIG.5(D) compared to FIG.5(C)).

[0133] These findings provide evidence that E6-induced degradation of PDZ proteins is important for its anti-apoptotic function and Prosβ6 and Prosβ2 inhibition, used separately or in combination) can interfere with this function of E6, promoting death. Furthermore, it demonstrates that the cytotoxicity effect of Prosβ6 and Prosβ2 co-inhibition involves both the PDZ-dependent and independent apoptotic cell death mechanisms.

[0134] Next, candidate genes whose functional inhibition enhances the PDZ-mediated cell death were sought. This search identified Drosophila Slmb (Human βTrCP), a well-conserved F-box protein of SCF (Skp1-Cullin 1-F-box protein) E3 ubiquitin ligase. When expression of Slmb was downregulated using an RNAi transgene, the PDZ-mediated cell death was dramatically enhanced (FIG.6(F) compared to FIG.6(E)). The effect was found to be specific to infected cells as slmb downregulation in the healthy tissue did not lead to any pathogenesis (FIG. 6(C)). These results suggested that PDZ-mediated apoptosis and apoptosis induced by slmb downregulation are two independent apoptotic cell death pathways that work synergistically. To further demonstrate this synergy, slmb was downregulated in the eye tissues expressing an intact E6 capable of degrading PDZ domain proteins and blocking cell death. Downregulation of slmb was able to interfere with the anti-apoptotic function of E6 in PDZ- independent manner (FIG.6(D) compared to FIG.6(B)). These results altogether indicated that cell death induced by PDZ proteins and slmb inhibition are two independent apoptotic pathways that work synergistically.

[0135] To evaluate the therapeutic potential of synergestic effect of PDZ-mediated apoptosis and that induced by slmb inhibition, the inhibition of proteasomal subunits which lead to PDZ- mediated death was combined with slmb inhibition. The results showed that even inhibition of just Prosβ6 in combination with slmb downregulation dramatically increased apoptotic cell death compared to individual inhibition of these targets (FIG.6(H) compared to FIG.6(D,G)). Taken together, these findings provide clear indications that Prosβ6, Prosβ2, and slmb co- inhibition induces independent apoptotic cell death mechanisms that work synergistically to eliminate the infected cells in a manner not harming the healthy cells. Thus, targeting Prosβ6, Prosβ2, and βTrCP individually or in combination may be used in molecularly-targeted treatments for HPV-associated cancers as well as for other PDZ targeting viral infections. Further results are shown in FIGS.7- 33 as described below.

[0136] Shown below are siRNA duplex sequences which are used in the experiments of FIGS. 7-33 to block PSMB1, PSMB7, and βTrCP activity. The lower case “r” preceding a residue indicates that the residue is a ribonucleotide, and the lack of a lower case “r” before a residue indicates that the residue is a deoxyribonucleotide (or deoxynucleotide). Therefore, certain sequences below (such as SEQ ID NOS:1, 3, 5, 7, 9, and 11) are hybrid constructs of both ribonucleotides and deoxyribonucleotides.

[0137] PSMB1 / β6 siRNA1 Duplex: 5' rGrUrCrUrUrArCrGrCrUrGrArCrArArArGrArUrUrArUrUGA 3' (SEQ ID NO:1) 5' rUrCrArArUrArArUrCrUrUrUrGrUrCrArGrCrGrUrArArGrArCrArG 3'. (SEQ ID NO:2)

[0138] PSMB1 / β6 siRNA2 Duplex: 5’rArGrArGrArArArCrCrUrGrArArGrUrArCrUrCrArArArAAA 3’ (SEQ ID NO:3) 5’ rUrUrUrUrUrUrGrArGrUrArCrUrUrCrArGrGrUrUrUrCrUrCrUrUrU 3 (SEQ ID NO:4)

[0139] PSMB7 / β2 siRNA1 Duplex: 5’ rArCrArUrUrGrArCrCrUrCrUrGrCrGrUrCrArUrCrArGrCAA 3’ (SEQ ID NO:5) 5’rUrUrGrCrUrGrArUrGrArCrGrCrArGrArGrGrUrCrArArUrGrUrUrG 3’. (SEQ ID NO:6)

[0140] PSMB1 / β2 siRNA2 Duplex: 5' rArGrUrArArGrArCrArCrUrCrArUrGrUrGrGrCrUrArGrUGT 3' (SEQ ID NO:7) 5' rArCrArCrUrArGrCrCrArCrArUrGrArGrUrGrUrCrUrUrArCrUrGrG 3' (SEQ ID NO:8)

[0141] βTrCP siRNA1 Duplex: 5’ rGrUrGrGrArUrUrCrUrCrArGrArCrArUrGrArUrArCrUrCTC 3’ (SEQ ID NO:9) 5’ rGrArGrArGrUrArUrCrArUrGrUrCrUrGrArGrArArUrCrCrArCrUrG 3’ (SEQ ID NO:10)

[0142] βTrCP siRNA2 Duplex: 5’ rGrGrArArGrArArGrCrUrUrArUrCrGrArGrArGrArArUrGGT 3’ (SEQ ID NO:11) 5’ rArCrCrArUrUrCrUrCrUrCrGrArUrArArGrCrUrUrCrUrUrCrCrArC 3’ (SEQ ID NO:12)

[0143] FIGS.7-8, 11, 13 and 14 show that siRNA-induced reduction of β6 results in death of HPV-positive cervical cancer cells of the cell lines SiHa and CaSki, while there was no effect on cells of the noncancerous cell lines END1 / E6E7 and ECT1 / E6E7. Two independent sets of β6 siRNA (β6 siRNA 1 Duplex and β6 siRNA 2 Duplex) were used for SiHa, while only one set of β6 siRNA (β6 siRNA 1 Duplex) was used for CaSki.

[0144] FIGS.9-10, 12, 15 and 16 show that siRNA-induced reduction of β2 results in death of HPV-positive cervical cancer cells of the cell lines SiHa and CaSki, while there was no effect on cells of the noncancerous cell lines END1 / E6E7 and ECT1 / E6E7. Two independent sets of β2 siRNA (β2 siRNA 1 Duplex and β2 siRNA 2 Duplex) were used for SiHa, while only one set of β2 siRNA (β2 siRNA 1 Duplex) was used for CaSki.

[0145] FIGS.17-18 show western blots which demonstrate the reduction of β6 by β6 siRNA 1 Duplex, and of β2 by β2 siRNA 1 Duplex and β2 siRNA 2 Duplex, respectively.

[0146] FIGS.19-22 show that siRNA-induced reduction of β6 results in death of HPV-positive oropharyngeal cancer cells of the cell lines SCC2 and SCC90, while there was no effect on cells of the noncancerous cell lines END1 / E6E7 and ECT1 / E6E7. FIGS. 23-26 show that siRNA-induced reduction of β2 results in death of HPV-positive oropharyngeal cancer cells of the cell lines SCC2 and SCC90, while there was no effect on cells of the noncancerous cell lines END1 / E6E7 and ECT1 / E6E7.

[0147] FIGS.27-28 show western blots which demonstrate the reduction of β6 by β6 siRNA 1 Duplex and β6 siRNA 2 Duplex, and of β2 by β2 siRNA 1 Duplex and β2 siRNA 2 Duplex, respectively.

[0148] FIG.29 shows results which assess the cytotoxicity effect of simultaneous reduction of proteasome subunits β6 (PSMB1) and β2 (PSMB7) in human cervical cells. When proteasome subunits β2 and β6 are knocked down simultaneously by siRNAs in HPV-positive SiHa human cervical cancer cells, the cytotoxic effect on the cells is greater than in single siRNA treatments of β6 or β2 alone. FIG. 30 shows results which assess the cytotoxicity effect of simultaneous reduction of proteasome subunits β6 (PSMB1) and β2 (PSMB7) in human oropharyngeal cells. When proteasome subunits β2 and β6 are knocked down simultaneously by siRNAs in HPV- positive SCC2 human oropharyngeal cancer cells, the cytotoxic effect on the cells is greater than in single siRNA treatments of β6 or β2 alone. In contrast, as shown in FIG. 31, simultaneous siRNA-induced knockdown of β2 and β6 has no effect on control noncancerous cells, ECT1 / E6E7.

[0149] FIG.32 shows the effect of the reduction of βTrCP by two siRNAs, βTrCP siRNA 1 Duplex and βTrCP siRNA 2 Duplex, on the HPV-positive cervical cancer cell line SiHA. siRNA-induced reduction of βTrCP results in death of HPV-positive cervical cancer cells in the SiHa cell line. FIG.33 shows that the siRNAs had no effect on noncancerous cervical cells in the END1 / E6E7 cell line.

[0150] In summary, PDZ targeting has been shown to be a component of viral pathogenesis. However, no therapeutics that target this main shared evolutionary mechanism of action have been demonstrated. The present results provide compelling evidence that PDZ targeting by HPV is a mechanism to evade cell death, and that inhibiting Prosβ6, Prosβ2, and / or βTrCP interferes with this function, thereby inducing cell death. Since PDZ targeting is a common evolutionary mechanism among viruses, these results demonstrate that the inhibition ofPSMB1(Prosβ6), PSMB7 (Prosβ2), and / or βTrCP inhibition, used singly, or in combination, can be used to eliminate viral infections based on PDZ targeting.

[0151] Hence, the impact of this discovery is highly significant as (1) PDZ targeting viruses including EBV, HPV, and HTLV-1 together account for 40% of all viral associated cancers; (2) currently there is no vaccine for EBV, HTLV-1 and HIV; and (3) for those PDZ targeting viruses against which there is a vaccine, such as for SARS-CoV-2, the current therapeutics are limited in efficacy. The benefits of the present work can be further expanded to cancer cells and viral- infected cells that show resistance to currently available Prosβ2 inhibitors such as Carfilzomib and Marizomib. Combination of current available Prosβ2 inhibitors with Prosβ6 or / and βTrCP inhibitors can thus provide novel combination therapies for such resistant cells.

[0152] The present results demonstrate that targeting Prosβ6, Prosβ2, and / or βTrCP can be used as a therapy for elimination of viral co-infected cells. Synergistic effects of viral co- infections is a significant health problem. Long COVID complication caused by SARS-CoV- 2, HIV, and HPV all cause reactivation of EBV to promote EBV-associated disorders. These co-infections have significantly increased the number of malignancies such as nasopharyngeal and lymphoma as well as autoimmune diseases such as multiple sclerosis and lupus. Together, these conditions have resulted in enormous economic burden with long COVID alone costing as much as $3.7 trillion since the COVID-19 pandemic.

[0153] In at least certain embodiments of the methods of the present disclosure, the viral disease-inducing virus is selected from the group consisting of HPV (Human Papillomavirus), Adenovirus, Influenza A, Human T-cell lymphotrophic virus type 1 (HTLV-1), Human Immunodeficiency virus (HIV), West Nile, Dengue, and Severe Acute Respiratory Syndrome- Coronavirus-2 (SARS-CoV-2), the inhibitor of Prosβ6 or Prosβ2 is selected from the group consisting of LU-102, LU-002c, MG-132, Bortezomib, Carfilzomib, Ixazomib, Marizomib, Oprozomib, Delanzomib, and an siRNA, and the inhibitor of βTrCP is selected from the group consisting of Acyclovir, Erioflorin, GS143, and PHAR.

[0154] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV and the inhibitor is LU-102.

[0155] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV and the inhibitor is LU-002c.

[0156] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV and the inhibitor is MG-132.

[0157] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV and the inhibitor is Bortezomib.

[0158] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV and the inhibitor is Carfilzomib.

[0159] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV and the inhibitor is Ixazomib.

[0160] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV and the inhibitor is Marizomib.

[0161] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV and the inhibitor is Oprozomib.

[0162] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV and the inhibitor is Delanzomib.

[0163] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV and the inhibitor is an siRNA.

[0164] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV and the inhibitor is Acyclovir.

[0165] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV and the inhibitor is Erioflorin.

[0166] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV and the inhibitor is GS143.

[0167] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV and the inhibitor is PHAR.

[0168] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is a high-risk strain of HPV and the inhibitor is LU-102.

[0169] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is a high-risk strain of HPV and the inhibitor is LU-002c.

[0170] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is a high-risk strain of HPV and the inhibitor is MG-132.

[0171] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is a high-risk strain of HPV and the inhibitor is Bortezomib.

[0172] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is a high-risk strain of HPV and the inhibitor is Carfilzomib.

[0173] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is a high-risk strain of HPV and the inhibitor is Ixazomib.

[0174] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is a high-risk strain of HPV and the inhibitor is Marizomib.

[0175] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is a high-risk strain of HPV and the inhibitor is Oprozomib.

[0176] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is a high-risk strain of HPV and the inhibitor is Delanzomib.

[0177] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is a high-risk strain of HPV and the inhibitor is an siRNA.

[0178] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is a high-risk strain of HPV and the inhibitor is Acyclovir.

[0179] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is a high-risk strain of HPV and the inhibitor is Erioflorin.

[0180] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is a high-risk strain of HPV and the inhibitor is GS143.

[0181] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is a high-risk strain of HPV and the inhibitor is PHAR.

[0182] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV 16 and the inhibitor is LU-102.

[0183] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV 16 and the inhibitor is LU-002c.

[0184] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV 16 and the inhibitor is MG-132.

[0185] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV 16 and the inhibitor is Bortezomib.

[0186] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV 16 and the inhibitor is Carfilzomib.

[0187] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV 16 and the inhibitor is Ixazomib.

[0188] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV 16 and the inhibitor is Marizomib.

[0189] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV 16 and the inhibitor is Oprozomib.

[0190] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV 16 and the inhibitor is Delanzomib.

[0191] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV 16 and the inhibitor is an siRNA.

[0192] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV 16 and the inhibitor is Acyclovir.

[0193] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV 16 and the inhibitor is Erioflorin.

[0194] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV 16 and the inhibitor is GS143.

[0195] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV 16 and the inhibitor is PHAR.

[0196] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV 18 and the inhibitor is LU-102.

[0197] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV 18 and the inhibitor is LU-002c.

[0198] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV 18 and the inhibitor is MG-132.

[0199] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV 18 and the inhibitor is Bortezomib.

[0200] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV 18 and the inhibitor is Carfilzomib.

[0201] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV 18 and the inhibitor is Ixazomib.

[0202] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV 18 and the inhibitor is Marizomib.

[0203] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV 18 and the inhibitor is Oprozomib.

[0204] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV 18 and the inhibitor is Delanzomib.

[0205] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV 18 and the inhibitor is an siRNA.

[0206] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV 18 and the inhibitor is Acyclovir.

[0207] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV 18 and the inhibitor is Erioflorin.

[0208] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV 18 and the inhibitor is GS143.

[0209] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HPV 18 and the inhibitor is PHAR.

[0210] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Adenovirus and the inhibitor is LU-102.

[0211] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Adenovirus and the inhibitor is LU-002c.

[0212] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Adenovirus and the inhibitor is MG-132.

[0213] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Adenovirus and the inhibitor is Bortezomib.

[0214] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Adenovirus and the inhibitor is Carfilzomib.

[0215] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Adenovirus and the inhibitor is Ixazomib.

[0216] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Adenovirus and the inhibitor is Marizomib.

[0217] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Adenovirus and the inhibitor is Oprozomib.

[0218] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Adenovirus and the inhibitor is Delanzomib.

[0219] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Adenovirus and the inhibitor is an siRNA.

[0220] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Adenovirus and the inhibitor is Acyclovir.

[0221] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Adenovirus and the inhibitor is Erioflorin.

[0222] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Adenovirus and the inhibitor is GS143.

[0223] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Adenovirus and the inhibitor is PHAR.

[0224] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Influenza A and the inhibitor is LU-102.

[0225] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Influenza A and the inhibitor is LU-002c.

[0226] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Influenza A and the inhibitor is MG-132.

[0227] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Influenza A and the inhibitor is Bortezomib.

[0228] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Influenza A and the inhibitor is Carfilzomib.

[0229] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Influenza A and the inhibitor is Ixazomib.

[0230] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Influenza A and the inhibitor is Marizomib.

[0231] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Influenza A and the inhibitor is Oprozomib.

[0232] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Influenza A and the inhibitor is Delanzomib.

[0233] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Influenza A and the inhibitor is an siRNA.

[0234] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Influenza A and the inhibitor is Acyclovir.

[0235] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Influenza A and the inhibitor is Erioflorin.

[0236] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Influenza A and the inhibitor is GS143.

[0237] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Influenza A and the inhibitor is PHAR.

[0238] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HTLV-1 and the inhibitor is LU-102.

[0239] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HTLV-1 and the inhibitor is LU-002c.

[0240] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HTLV-1 and the inhibitor is MG-132.

[0241] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HTLV-1 and the inhibitor is Bortezomib.

[0242] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HTLV-1 and the inhibitor is Carfilzomib.

[0243] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HTLV-1 and the inhibitor is Ixazomib.

[0244] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HTLV-1 and the inhibitor is Marizomib.

[0245] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HTLV-1 and the inhibitor is Oprozomib.

[0246] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HTLV-1 and the inhibitor is Delanzomib.

[0247] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HTLV-1 and the inhibitor is an siRNA.

[0248] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HTLV-1 and the inhibitor is Acyclovir.

[0249] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HTLV-1 and the inhibitor is Erioflorin.

[0250] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HTLV-1 and the inhibitor is GS143.

[0251] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HTLV-1 and the inhibitor is PHAR.

[0252] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HIV and the inhibitor is LU-102.

[0253] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HIV and the inhibitor is LU-002c.

[0254] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HIV and the inhibitor is MG-132.

[0255] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HIV and the inhibitor is Bortezomib.

[0256] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HIV and the inhibitor is Carfilzomib.

[0257] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HIV and the inhibitor is Ixazomib.

[0258] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HIV and the inhibitor is Marizomib.

[0259] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HIV and the inhibitor is Oprozomib.

[0260] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HIV and the inhibitor is Delanzomib.

[0261] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HIV and the inhibitor is an siRNA.

[0262] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HIV and the inhibitor is Acyclovir.

[0263] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HIV and the inhibitor is Erioflorin.

[0264] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HIV and the inhibitor is GS143.

[0265] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HIV and the inhibitor is PHAR.

[0266] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is West Nile and the inhibitor is LU-102.

[0267] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is West Nile and the inhibitor is LU-002c.

[0268] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is West Nile and the inhibitor is MG-132.

[0269] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is West Nile and the inhibitor is Bortezomib.

[0270] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is West Nile and the inhibitor is Carfilzomib.

[0271] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is West Nile and the inhibitor is Ixazomib.

[0272] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is West Nile and the inhibitor is Marizomib.

[0273] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is West Nile and the inhibitor is Oprozomib.

[0274] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is West Nile and the inhibitor is Delanzomib.

[0275] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is West Nile and the inhibitor is an siRNA.

[0276] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HIV and the inhibitor is Acyclovir.

[0277] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HIV and the inhibitor is Erioflorin.

[0278] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HIV and the inhibitor is GS143.

[0279] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is HIV and the inhibitor is PHAR.

[0280] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Dengue and the inhibitor is LU-102.

[0281] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Dengue and the inhibitor is LU-002c.

[0282] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Dengue and the inhibitor is MG-132.

[0283] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Dengue and the inhibitor is Bortezomib.

[0284] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Dengue and the inhibitor is Carfilzomib.

[0285] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Dengue and the inhibitor is Ixazomib.

[0286] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Dengue and the inhibitor is Marizomib.

[0287] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Dengue and the inhibitor is Oprozomib.

[0288] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Dengue and the inhibitor is Delanzomib.

[0289] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Dengue and the inhibitor is an siRNA.

[0290] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Dengue and the inhibitor is Acyclovir.

[0291] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Dengue and the inhibitor is Erioflorin.

[0292] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Dengue and the inhibitor is GS143.

[0293] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is Dengue and the inhibitor is PHAR.

[0294] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is SARS-CoV-2 and the inhibitor is LU-102.

[0295] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is SARS-CoV-2 and the inhibitor is LU-002c.

[0296] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is SARS-CoV-2 and the inhibitor is MG-132.

[0297] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is SARS-CoV-2 and the inhibitor is Bortezomib.

[0298] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is SARS-CoV-2 and the inhibitor is Carfilzomib.

[0299] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is SARS-CoV-2 and the inhibitor is Ixazomib.

[0300] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is SARS-CoV-2 and the inhibitor is Marizomib.

[0301] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is SARS-CoV-2 and the inhibitor is Oprozomib.

[0302] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is SARS-CoV-2 and the inhibitor is Delanzomib.

[0303] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is SARS-CoV-2 and the inhibitor is an siRNA.

[0304] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is SARS-CoV-2 and the inhibitor is Acyclovir.

[0305] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is SARS-CoV-2 and the inhibitor is Erioflorin.

[0306] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is SARS-CoV-2 and the inhibitor is GS143.

[0307] In at least one embodiment of the presently disclosed method of treating a viral disease, the viral disease-inducing virus is SARS-CoV-2 and the inhibitor is PHAR.

[0308] In at least certain embodiments, the present disclosure is directed to a method of treating a viral disease associated with targeting of PDZ domain proteins or a Ubiquitin-Proteasome System (UPS) by a viral disease-inducing virus, in a subject in need of such therapy, comprising administering to the subject an inhibitor of at least one of 20s proteasome subunit β6 (Prosβ6), 20s proteasome subunit β2 (Prosβ2), and β-Transducin repeat-containing protein (βTrCP), thereby causing the death of cells that have been infected by the viral disease-inducing virus.The viral disease-inducing virus may be HPV, Adenovirus, Influenza A, HTLV-1, HIV, West Nile, Dengue, or SARS-CoV. The HPV may be a high-risk strain of HPV. The HPV may be HPV 16 or HPV 18. The inhibitor of Prosβ6 or Prosβ2 may be LU-102, LU-002c, MG-132, Bortezomib, Carfilzomib, Ixazomib, Marizomib, Oprozomib, Delanzomib, or an siRNA. The inhibitor of βTrCP may be Acyclovir, Erioflorin, GS143, and PHAR.

[0309] In other embodiments, the present disclosures is directed to a method of treating a Human Papillomavirus (HPV)-associated disease in a subject in need of such therapy, comprising administering to the subject an inhibitor of at least one of 20s proteasome subunit β6 (Prosβ6), 20s proteasome subunit β2 (Prosβ2), and β-Transducin repeat-containing protein (βTrCP), thereby causing the death of cells that have been infected by the HPV. The HPV may be a high-risk strain of HPV. The HPV may be HPV 16 or HPV 18. The high-risk HPV strain may be selected from HPV strains 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. The inhibitor of Prosβ6 or Prosβ2 may be LU-102, LU-002c, MG-132, Bortezomib, Carfilzomib, Ixazomib, Marizomib, Oprozomib, Delanzomib, or an siRNA. The inhibitor of βTrCP may be Acyclovir, Erioflorin, GS143, and PHAR.

[0310] In other embodiments, the present disclosures is directed to a method of treating a disease or condition associated with expression of Human Papillomavirus (HPV) oncogene E6, in a subject in need of such therapy, comprising administering to the subject an inhibitor of at least one of 20s proteasome subunit β6 (Prosβ6), 20s proteasome subunit β2 (Prosβ2), and β- Transducin repeat-containing protein (βTrCP), thereby causing the death of HPV oncogene E6- expressing cells. The HPV oncogene E6-expressing cells may comprise HPV oncoprotein E6 and Human ubiquitin ligase protein E3A (hUBE3A). The HPV may be a high-risk strain of HPV. The HPV may be HPV 16 or HPV 18. The high-risk HPV strain may be selected from HPV strains 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. The inhibitor of Prosβ6 or Prosβ2 may be LU-102, LU-002c, MG-132, Bortezomib, Carfilzomib, Ixazomib, Marizomib, Oprozomib, Delanzomib, or an siRNA. The inhibitor of βTrCP may be Acyclovir, Erioflorin, GS143, and PHAR. The disease or condition may be an HPV-induced cancer. The HPV- induced cancer may be a cervical, head and neck, mouth, tongue, oropharyngeal, anal, vulvar, vaginal, or penile cancer.

[0311] In other embodiments, the present disclosure is directed to a method of inhibiting growth of human papillomavirus (HPV)-induced cancer cells, comprising exposing the HPV- induced cancer cells to an inhibitor of at least one of 20s proteasome subunit β6 (Prosβ6), 20s proteasome subunit β2 (Prosβ2), and β-Transducin repeat-containing protein (βTrCP). The HPV-induced cancer cells may be cervical, head and neck, mouth, tongue, oropharyngeal, anal,vulvar, vaginal, and penile cancer cells. The HPV may be a high-risk strain of HPV. The HPV may be HPV 16 or HPV 18. The high-risk HPV strain may be selected from HPV strains 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. The inhibitor of Prosβ6 or Prosβ2 may be LU- 102, LU-002c, MG-132, Bortezomib, Carfilzomib, Ixazomib, Marizomib, Oprozomib, Delanzomib, or an siRNA. The inhibitor of βTrCP may be Acyclovir, Erioflorin, GS143, and PHAR. The HPV-induced cancer cells may be treated in vivo. The HPV-induced cancer cells may be treated in vitro.

[0312] While the present disclosure has been described herein in connection with certain embodiments so that aspects thereof may be more fully understood and appreciated, it is not intended that the present disclosure be limited to these particular embodiments. On the contrary, it is intended that all alternatives, modifications and equivalents are included within the scope of the present disclosure as defined herein. Thus the examples described above, which include particular embodiments, will serve to illustrate the practice of the inventive concepts of the present disclosure, it being understood that the particulars shown are by way of example and for purposes of illustrative discussion of particular embodiments only and are presented in the cause of providing what is believed to be the most useful and readily understood description of procedures as well as of the principles and conceptual aspects of the present disclosure.

[0313] Changes may be made in the formulations, compounds, and compositions described herein, the methods described herein or in the steps or the sequence of steps of the methods described herein without departing from the spirit and scope of the present disclosure. Further, while various embodiments of the present disclosure have been described in claims herein below, it is not intended that the present disclosure be limited to these particular claims.

Claims

What is claimed is:

1. A method of treating a viral disease associated with targeting of PDZ domain proteins or a Ubiquitin-Proteasome System (UPS) by a viral disease-inducing virus, in a subject in need of such therapy, the method comprising: administering to the subject at least one inhibitor of at least one of 20s proteasome subunit β6 (Prosβ6), 20s proteasome subunit β2 (Prosβ2), and β-Transducin repeat-containing protein (βTrCP), thereby causing the death of cells that have been infected by the viral disease-inducing virus.

2. The method of claim 1, wherein the viral disease-inducing virus is selected from the group consisting of HPV (Human Papillomavirus), Adenovirus, Influenza A, Human T-cell lymphotrophic virus type 1 (HTLV-1), Human Immunodeficiency virus (HIV), West Nile, Dengue, and Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2).

3. The method of claim 2, wherein the HPV is a high-risk strain of HPV.

4. The method of claim 2, wherein the HPV is HPV 16 or HPV 18.

5. The method of claim 1, wherein the inhibitor of Prosβ6 or Prosβ2 is selected from the group consisting of LU-102, LU-002c, MG-132, Bortezomib, Carfilzomib, Ixazomib, Marizomib, Oprozomib, Delanzomib, an siRNA, and combinations thereof.

6. The method of claim 1, wherein the inhibitor of βTrCP is selected from the group consisting of Acyclovir, Erioflorin, GS143, PHAR, and combinations thereof.

7. A method of treating a Human Papillomavirus (HPV)-associated disease in a subject in need of such therapy, the method comprising: administering to the subject at least one inhibitor of at least one of 20s proteasome subunit β6 (Prosβ6), 20s proteasome subunit β2 (Prosβ2), and β-Transducin repeat-containing protein (βTrCP), thereby causing the death of cells that have been infected by the HPV.

8. The method of claim 7, wherein the HPV is high-risk strain of HPV.

9. The method of claim 7, wherein the HPV is HPV 16 or HPV 18.

10. The method of claim 7, wherein the at least one inhibitor of Prosβ6 or Prosβ2 is selected from the group consisting of LU-102, LU-002c, MG-132, Bortezomib, Carfilzomib, Ixazomib, Marizomib, Oprozomib, Delanzomib, an siRNA, and combinations thereof.

11. The method of claim 7, wherein the at least one inhibitor of βTrCP is selected from the group consisting of Acyclovir, Erioflorin, GS143, PHAR, and combinations thereof.

12. A method of treating a disease or condition associated with expression of Human Papillomavirus (HPV) oncogene E6, in a subject in need of such therapy, the method comprising: administering to the subject at least one inhibitor of at least one of 20s proteasome subunit β6 (Prosβ6), 20s proteasome subunit β2 (Prosβ2), and β-Transducin repeat-containing protein (βTrCP), thereby causing the death of HPV oncogene E6-expressing cells.

13. The method of claim 12, wherein the HPV oncogene E6-expressing cells comprise HPV oncoprotein E6 and Human ubiquitin ligase protein E3A (hUBE3A).

14. The method of claim 12, wherein the HPV is high-risk strain.

15. The method of claim 12, wherein the HPV is HPV 16 or HPV 18.

16. The method of claim 12, wherein the at least one inhibitor of Prosβ6 or Prosβ2 is selected from the group consisting of LU-102, LU-002c, MG-132, Bortezomib, Carfilzomib, Ixazomib, Marizomib, Oprozomib, Delanzomib, an siRNA, and combinations thereof.

17. The method of claim 12, wherein the at least one inhibitor of βTrCP is selected from the group consisting of Acyclovir, Erioflorin, GS143, PHAR, and combinations thereof.

18. The method of claim 12, wherein the disease or condition is an HPV-induced cancer.

19. The method of claim 12, wherein the HPV-induced cancer is selected from the group consisting of cervical, head and neck, mouth, tongue, oropharyngeal, anal, vulvar, vaginal, and penile cancers, and combinations thereof.

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