Small Molecule Inhibitors of Human Papillomavirus Protein - Protein Interactions

D’Abramo, Claudia M.; Archambault, Jacques

doi:10.2174/1874357901105010080

Cited by 69 publications

(57 citation statements)

References 167 publications

(159 reference statements)

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“…Since E1 is the only viral protein with enzymatic activities, it is an attractive target for development of novel therapeutic agents to treat HPV-associated benign lesions where the whole viral life cycle is completed. Indeed, some candidate small molecules have been reported to inhibit the E1 function (5,9,15,(40)(41)(42). However, their identification and evaluation was done using biochemical assays or surrogate cell-based assays, and a true antiviral activity has yet to be tested.…”

Section: Discussionmentioning

confidence: 99%

The E1 Protein of Human Papillomavirus Type 16 Is Dispensable for Maintenance Replication of the Viral Genome

Egawa¹,

Nakahara²,

Ohno³

et al. 2012

J Virol

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dPapillomavirus genomes are thought to be amplified to about 100 copies per cell soon after infection, maintained constant at this level in basal cells, and amplified for viral production upon keratinocyte differentiation. To determine the requirement for E1 in viral DNA replication at different stages, an E1-defective mutant of the human papillomavirus 16 (HPV16) genome featuring a translation termination mutation in the E1 gene was used. The ability of the mutant HPV16 genome to replicate as nuclear episomes was monitored with or without exogenous expression of E1. Unlike the wild-type genome, the E1-defective HPV16 genome became established in human keratinocytes only as episomes in the presence of exogenous E1 expression. Once established, it could replicate with the same efficiency as the wild-type genome, even after the exogenous E1 was removed. However, upon calcium-induced keratinocyte differentiation, once again amplification was dependent on exogenous E1. These results demonstrate that the E1 protein is dispensable for maintenance replication but not for initial and productive replication of HPV16. P apillomaviruses (PVs) are small, double-stranded DNA viruses that infect stratified squamous epithelium. Human PVs (HPVs) are very important causative agents for various lesions, ranging from verrucas to cancer. Among them, a subset of HPVs, the so-called high-risk types such as type 16 and 18, are associated with more than 90% of all cervical carcinomas as primary etiological factors (45). PVs establish long-term persistent infections in squamous epithelium, and the viral life cycle is tightly linked with the differentiation state of the host keratinocytes (7).PV genome is replicated and amplified in three different stages: establishment, maintenance, and productive stages of the life cycle. In the establishment stage, soon after infection of the basal layer keratinocytes, a single or a few initial copies of the viral genome amplify and establish residence as multicopy circular extrachromosomal elements (episomes) in the nucleus. In the maintenance stage, the viral genomes in each affected cell replicate approximately once in a cell cycle in proliferating basal layer keratinocytes. Then, in the productive stage, they are exponentially amplified in terminally differentiating keratinocytes and packaged into progeny virions. It is important to understand the molecular mechanisms underlying this triphasic model for development of new therapies against HPV-infected lesions, such as cervical intraepithelial neoplasias, which can progress to cervical cancer.The regulation of viral DNA replication is thought to differ in these three distinct stages of the viral life cycle. Studies of lesions experimentally induced by rabbit oral papillomavirus (ROPV) infection showed that the genome copy number of ROPV is low in the basal layer and increases up to four orders of magnitude during the terminal differentiation of host keratinocytes (21). This corresponds to more than 13 rounds of continuous replication of the viral ...

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Section: Discussionmentioning

confidence: 99%

The E1 Protein of Human Papillomavirus Type 16 Is Dispensable for Maintenance Replication of the Viral Genome

Egawa¹,

Nakahara²,

Ohno³

et al. 2012

J Virol

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“…E1 and E2) that are required for viral genome replication during the HPV productive cycle (Fig. 9A) (D'Abramo and Archambault, 2011;McBride, 2013;Bergvall et al, 2013). E1 is the most highly conserved HPV protein and the only one with enzymatic activity.…”

Section: Route Of Administration Clinical Indicationmentioning

confidence: 99%

Insights into the mechanism of action of cidofovir and other acyclic nucleoside phosphonates against polyoma- and papillomaviruses and non-viral induced neoplasia

et al. 2015

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Acyclic nucleoside phosphonates (ANPs) are well-known for their antiviral properties, three of them being approved for the treatment of human immunodeficiency virus infection (tenofovir), chronic hepatitis B (tenofovir and adefovir) or human cytomegalovirus retinitis (cidofovir). In addition, cidofovir is mostly used off-label for the treatment of infections caused by several DNA viruses other than cytomegalovirus, including papilloma- and polyomaviruses, which do not encode their own DNA polymerases. There is considerable interest in understanding why cidofovir is effective against these small DNA tumor viruses. Considering that papilloma- and polyomaviruses cause diseases associated either with productive infection (characterized by high production of infectious virus) or transformation (where only a limited number of viral proteins are expressed without synthesis of viral particles), it can be envisaged that cidofovir may act as antiviral and/or antiproliferative agent. The aim of this review is to discuss the advances in recent years in understanding the mode of action of ANPs as antiproliferative agents, given the fact that current data suggest that their use can be extended to the treatment of non-viral related malignancies.

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“…E1 is a helicase and the only enzyme encoded by HPV [26]. It can interact with host DNA replication machinery [27-29], induce DNA damage, and mitigate host defence [7, 30].…”

Section: Discussionmentioning

confidence: 99%

Elevated HPV16 E1 Expression Is Associated with Cervical Cancer Progression

2017

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Objectives: The primary replication protein, HPV E1, has been shown to play a role in mitigating host defence and disrupting normal cell cycle processes, leading to the development of cancer. This study investigated the expression profile of HPV16 E1 in various stages of cervical cancer development and the factors that control E1 expression. Methods: One hundred and twenty-four HPV16-positive cervical samples ranging from normal to CIN 1, CIN 2/3, and SCC lesions were studied. E1 mRNA expression was determined by ddPCR. Methylation of promoters p97 and p670 was quantified by pyrosequencing, while PCR, qPCR, and sequencing were used to determine the physical state and variations of the HPV16 E1 genome. Results: Increased E1 mRNA expression related to disease progression (normal 0.18, CIN 1 0.41, CIN 2/3 0.65, and SCC 0.79) was demonstrated with a significant positive correlation (r = 0.661, p = 0.019). No association between physical state and E1 expression was found. Methylation of p97 and p670 promoters showed significant elevation in SCC compared to normal samples. Only 4.2% showed genomic variations of HPV16 E1 63-bp duplication. Conclusion: E1 may play a role in cancer development. The detection of E1 mRNA and promoter methylation may be useful as cancer prognostic markers.

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Small Molecule Inhibitors of Human Papillomavirus Protein - Protein Interactions

Cited by 69 publications

References 167 publications

The E1 Protein of Human Papillomavirus Type 16 Is Dispensable for Maintenance Replication of the Viral Genome

The E1 Protein of Human Papillomavirus Type 16 Is Dispensable for Maintenance Replication of the Viral Genome

Insights into the mechanism of action of cidofovir and other acyclic nucleoside phosphonates against polyoma- and papillomaviruses and non-viral induced neoplasia

Elevated HPV16 E1 Expression Is Associated with Cervical Cancer Progression

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