New Hope for HPV Treatment: SRPIN340
SRPIN340 shows promise in reducing HPV16 protein production and supporting cell health.
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Table of Contents
Human papillomaviruses (HPVs) are viruses that spread through sexual contact. They can infect the skin and mucous membranes, which are the thin layers of tissue lining the body. While most HPV infections do not cause any symptoms and get cleared by the immune system, some types are more dangerous. Notably, HPV types 16 and 18 are linked to serious health issues like cancer in areas such as the cervix, throat, and genital region. These two types are responsible for around 70% of cervical cancer cases worldwide.
To combat the threat posed by these high-risk strains of HPV, vaccines have been developed and provided to young people before they become sexually active. However, these vaccines only prevent infections; they do not treat existing ones. This creates a need for antiviral treatments to help those already infected with high-risk HPV types.
The Life Cycle of HPV
The life cycle of HPV is closely tied to the type of cells it infects, particularly the skin and mucous membrane cells. It involves complex interactions between the virus and the host cells. Some early proteins, known as E1 and E2, play crucial roles in allowing the virus to replicate itself. E1 and E2 are first made in the lower layers of the infected tissue to start the infection and later produced in the upper layers to aid in the production of new virus particles before they leave the host cells.
The E2 protein also acts as a transcription factor, which helps in controlling how genes are expressed. Other Viral Proteins like E6 and E7 are involved throughout the infection process. They drive the host cells to divide more quickly and prevent them from dying. This disruption can lead to the abnormal growth of cells and potentially cancer.
As the virus matures, late proteins such as L1 and L2 are produced. These proteins help form the outer shell of the virus and are made only in the uppermost layers of the epithelium to prevent the immune system from detecting the virus.
How Viruses Use Host Cell Processes
Viruses like HPV rely on the host cell's machinery to produce their proteins. A key aspect of this process is how cells splice their RNA, a step needed to make mature messenger RNA (mRNA) from RNA transcripts. The splicing process is directed by special proteins known as splicing factors, which determine how the RNA is pieced together.
These splicing factors are important because they can enhance the production of certain mRNA varieties from one gene. The splicing process is tightly regulated. One group of splicing factors, known as serine-arginine-rich splicing factors (SRSFs), is vital in controlling which parts of the RNA get included or excluded during splicing.
SRPIN340: A Potential Treatment
SRPIN340 is a compound designed to inhibit SRPK1, an important enzyme that modifies SRSFs. This modification influences how SRSFs function and where they are located in the cell. SRPIN340 has shown promise as a treatment in various viral infections, including HIV and hepatitis C.
The exploration of SRPIN340's effects on HPV is crucial due to its potential as a treatment option. Research looked into how this drug might affect the life cycle of HPV16, which is the most common and dangerous type of HPV.
Experimental Studies
Researchers aimed to see if SRPIN340 could reduce the production of HPV proteins in infected cells. They used a type of cell called NIKS16, which is designed to study HPV16. They tested SRPIN340 to see its impact on the expression of essential viral proteins and if it affected the cells' health.
Effect on E2 Protein
One of the main targets was the E2 protein, which is necessary for the virus's ability to replicate. The results showed that treatment with SRPIN340 decreased the levels of E2. This led to less production of other late viral proteins like L1 and E4, indicating that SRPIN340 effectively interfered with HPV's ability to produce new viruses.
Influence on Host Cell Function
Importantly, the treatment did not significantly affect the production of early viral RNA or proteins. While the drug impaired the late stages of the virus's life cycle, it left early processes largely untouched.
Moreover, the researchers confirmed that the treatment did not harm the infected cells or disrupt their growth. Overall cell health remained stable during the short-term exposure to SRPIN340, even at higher doses.
Safety Profile of SRPIN340
An essential aspect of any potential therapy is its safety. Researchers assessed how SRPIN340 affected both HPV-infected and uninfected cells. They found that the drug did not negatively impact cell growth or viability.
Gene Expression
Changes inWhen looking at the effects of SRPIN340 at a broader level, there were notable changes in gene expression in treated cells compared to untreated ones. The treatment caused an increase in genes related to skin cell differentiation and immune response. This is encouraging as it suggests that SRPIN340 could help restore normal cell functions disrupted by HPV infection.
Implications for Treatment
By inhibiting SRPK1, SRPIN340 offers a dual approach against HPV: reducing the virus's ability to proliferate and promoting healthier cell functions. This could be particularly important for individuals infected with high-risk HPVs who have not been vaccinated.
Overall, the findings suggest that SRPIN340 may be a promising candidate for further research as an antiviral treatment for HPV. Its ability to target host cell processes may offer an alternative route for controlling HPV infections in a way that traditional vaccines cannot.
Conclusion
In summary, SRPIN340 shows potential as a treatment for HPV16 by targeting essential host factors involved in viral replication and gene expression. This approach not only limits the virus's ability to thrive but also seems to promote healthier cell behavior, which could have positive implications for infected individuals. As researchers continue to investigate this compound, it may pave the way for new therapies for those affected by HPVs. Further studies and clinical trials will be vital in determining the effectiveness and safety of SRPIN340 in treating HPV and potentially other viral infections.
Title: The splicing factor kinase, SR protein kinase 1 (SRPK1) is essential for late events in the human papillomavirus life cycle.
Abstract: Human papillomaviruses (HPV) infect epithelial causing benign lesions. However, the so-called "high risk" HPVs that infect the anogenital regions and the oropharynx can cause precancerous lesions that can progress to malignant tumours. Understanding the HPV life cycle is important to the discovery of novel antiviral therapies. HPV uses cellular splicing for the production of the full suite of viral mRNAs. Members of the serine/arginine rich (SR) protein family can positively regulate splicing. SR protein activity and cellular location is regulated by kinases through phosphorylation of their serine-arginine domains. SR protein kinase 1 (SRPK1) phosphorylates SR proteins to licence their nuclear entry and can promote nuclear splicing in conjunction with another SR protein kinase, Clk1. SRPIN340 is a specific SRPK1 inhibitor that has been reported to inhibit replication of HCV, Sindbis virus and HIV. Using organotypic raft cultures supporting the HPV16 life cycle, we show that SRPIN340 inhibits the expression of the viral replication and transcription factor, E2. Drug-mediated loss of E2 is specifically associated with inhibition of late gene expression since early gene expression is unaffected. RNA sequencing revealed that SRPIN340 treatment resulted in many gene expression changes opposite to those induced by HPV16 infection. In particular, the loss of epithelial barrier structure and immune function was restored. SRPIN340 treatment resulted in changes in alternative splicing of 935 RNAs and pathway analysis showed a predominance of changes to RNAs encoding proteins involved in chromatin conformation, DNA repair and RNA processing. SRPIN340 treatment was not associated with changes in proliferation or differentiation of keratinocytes. Collectively, these results provide evidence that SRPK1 is a host factor that is essential for HPV16 replication and therefore, targeting this factor, or the phosphorylation events it mediates, could be considered as a therapeutic strategy for HPV16 infection. AUTHOR SUMMARYHuman papillomavirus (HPV) can cause precancerous and cancerous tumours of the anogenital region, for example, the cervix. HPV infects epithelial cells and utilizes the host cell gene expression machinery to produce its own proteins. Splicing is a key mechanism used by HPV to synthesise messenger RNAs that encode the viral proteins. Splicing is positively controlled by SR proteins which require to be phosphorylated by SR protein kinase (SRPK) to enter the nucleus and regulate splicing. SRPIN340 is a specific inhibitor of SRPK. SRPIN340 treatment of HPV16-infected epithelial cells resulted in loss of expression of the viral replication and transcription factor, E2 and abrogation of late events in the viral life cycle. SRPIN340 treatment counteracted some gene expression changes to the epithelium known to be cause by HPV infection. These data suggest that SRPK1 is essential for the HPV life cycle and that it could be a potential anti-viral target.
Authors: Sheila Graham, A. A. A. Faizo, C. Bellward, H. Hernandez-Lopez, A. Stevenson, Q. Gu
Last Update: 2024-11-04 00:00:00
Language: English
Source URL: https://www.biorxiv.org/content/10.1101/2024.10.28.620581
Source PDF: https://www.biorxiv.org/content/10.1101/2024.10.28.620581.full.pdf
Licence: https://creativecommons.org/licenses/by/4.0/
Changes: This summary was created with assistance from AI and may have inaccuracies. For accurate information, please refer to the original source documents linked here.
Thank you to biorxiv for use of its open access interoperability.