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Is viral E6 oncoprotein a viable target? A critical analysis in the context of cervical cancer
Avinash Kumar1, Ekta Rathi1, Raghu Chandrashekar Hariharapura2
1Department of Pharmaceutical Chemistry, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India.
Abstract:
An understanding of the pathology of cervical cancer (CC) mediated by E6/E7 oncoproteins of high-risk human papillomavirus (HPV) was developed by late 80's. But if we look at the present scenario, not a single drug could be developed to inhibit these oncoproteins and in turn, be used specifically for the treatment of CC. The readers are advised not to presume the "viability of E6 protein" as mentioned in the title relates to just druggability of E6. The viability aspect will cover almost everything a researcher should know to develop E6 inhibitors until the preclinical stage. Herein, we have analysed the achievements and shortcomings of the scientific community in the last four decades in targeting HPV E6 against CC. Role of all HPV proteins has been briefly described for better perspective with a little detailed discussion of the role of E6. We have reviewed the articles from 1985 onward, reporting in vitro inhibition of E6. Recently, many computational studies have reported potent E6 inhibitors and these have also been reviewed. Subsequently, a critical analysis has been reported to cover the in vitro assay protocols and in vivo models to develop E6 inhibitors. A paragraph has been devoted to the role of public policy to fight CC employing vaccines and whether the vaccine against HPV has quenched the zeal to develop drugs against it. The review concludes with the challenges and the way forward.
Insights
Despite understanding cervical cancer (CC) pathology, no drugs target high-risk human papillomavirus (HPV) E6/E7 oncoproteins. This review analyzes four decades of research on HPV E6 inhibitors for CC treatment.
Area of Science:
- Oncology
- Virology
- Drug Discovery
Background:
- Cervical cancer (CC) pathology involving high-risk human papillomavirus (HPV) E6/E7 oncoproteins understood since the late 1980s.
- Lack of approved drugs specifically targeting these oncoproteins for CC treatment remains a significant challenge.
- The 'viability of E6 protein' encompasses comprehensive knowledge for developing E6 inhibitors up to the preclinical stage.
Purpose of the Study:
- To critically analyze the scientific community's achievements and shortcomings over four decades in targeting HPV E6 for CC.
- To review advancements in inhibiting HPV E6 oncoproteins, including in vitro and computational studies.
- To assess in vitro assay protocols, in vivo models, and the impact of public policy and HPV vaccination on drug development efforts.
Main Methods:
- Systematic review of scientific literature from 1985 onwards focusing on HPV E6 inhibition for CC.
- Analysis of published in vitro inhibition studies and recent computational studies identifying potent E6 inhibitors.
- Critical evaluation of in vitro assay protocols, in vivo models, and the role of public policy and HPV vaccines.
Main Results:
- Despite extensive research, no drugs have been successfully developed to inhibit HPV E6/E7 oncoproteins for cervical cancer treatment.
- Numerous in vitro and computational studies have identified potential E6 inhibitors, but translation to clinical success is limited.
- The review highlights gaps in assay protocols, in vivo models, and discusses the complex interplay between vaccination and therapeutic drug development.
Conclusions:
- Significant challenges persist in developing effective E6 inhibitors for cervical cancer, necessitating further research and strategic development.
- A comprehensive understanding of E6 protein viability and improved preclinical models are crucial for advancing E6 inhibitor development.
- Future efforts should address existing shortcomings and explore novel strategies to overcome hurdles in targeting HPV oncoproteins for CC therapy.
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