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Targeting human papillomavirus genome replication for antiviral drug discovery.

ABSTRACT: Human papillomavirus (HPV) infections are a major human health problem; they are the cause of recurrent benign warts and of several cancers of the anogenital tract and head and neck region. Although there are two prophylactic HPV vaccines that could, if used universally, prevent as many as two-thirds of HPV-induced cancers, as well as several cytotoxic and immunomodulatory agents for localized treatment of infections, there are currently no HPV antiviral drugs in our arsenal of therapeutic agents. This review examines the status of past and ongoing research into the development of HPV antivirals, focused primarily upon approaches targeting the replication of the viral genome. The only HPV enzyme, E1, is a DNA helicase that interfaces with the cellular DNA replication machinery to replicate the HPV genome. To date, searches for small molecule inhibitors of E1 for use as antivirals have met with limited success. The lack of other viral enzymes has meant that the search for antivirals has shifted to a large degree to the modulation of protein-protein interactions. There has been some success in identifying small molecule inhibitors targeting interactions between HPV proteins but with activity against a small subset of viral types only. As noted in this review, it is thought that targeting E1 interactions with cellular replication proteins may provide inhibitors with broader activity against multiple HPV types. Herein, we outline the steps in HPV DNA replication and discuss those that appear to provide the most advantageous targets for the development of anti-HPV therapeutics.

SUBMITTER: Archambault J

PROVIDER: S-EPMC4658057 | biostudies-other | 2013

REPOSITORIES: biostudies-other

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Targeting human papillomavirus genome replication for antiviral drug discovery.

Archambault Jacques J Melendy Thomas T

Antiviral therapy 20130424 3

Human papillomavirus (HPV) infections are a major human health problem; they are the cause of recurrent benign warts and of several cancers of the anogenital tract and head and neck region. Although there are two prophylactic HPV vaccines that could, if used universally, prevent as many as two-thirds of HPV-induced cancers, as well as several cytotoxic and immunomodulatory agents for localized treatment of infections, there are currently no HPV antiviral drugs in our arsenal of therapeutic agent ...[more]

PMID: 23615820

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Project description:BackgroundThe emergence and continued global spread of the current COVID-19 pandemic has highlighted the need for methods to identify novel or repurposed therapeutic drugs in a fast and effective way. Despite the availability of methods for the discovery of antiviral drugs, the majority tend to focus on the effects of such drugs on a given virus, its constituent proteins, or enzymatic activity, often neglecting the consequences on host cells. This may lead to partial assessment of the efficacy of the tested anti-viral compounds, as potential toxicity impacting the overall physiology of host cells may mask the effects of both viral infection and drug candidates. Here we present a method able to assess the general health of host cells based on morphological profiling, for untargeted phenotypic drug screening against viral infections.ResultsWe combine Cell Painting with antibody-based detection of viral infection in a single assay. We designed an image analysis pipeline for segmentation and classification of virus-infected and non-infected cells, followed by extraction of morphological properties. We show that this methodology can successfully capture virus-induced phenotypic signatures of MRC-5 human lung fibroblasts infected with human coronavirus 229E (CoV-229E). Moreover, we demonstrate that our method can be used in phenotypic drug screening using a panel of nine host- and virus-targeting antivirals. Treatment with effective antiviral compounds reversed the morphological profile of the host cells towards a non-infected state.ConclusionsThe phenomics approach presented here, which makes use of a modified Cell Painting protocol by incorporating an anti-virus antibody stain, can be used for the unbiased morphological profiling of virus infection on host cells. The method can identify antiviral reference compounds, as well as novel antivirals, demonstrating its suitability to be implemented as a strategy for antiviral drug repurposing and drug discovery.

Dataset Information

Targeting human papillomavirus genome replication for antiviral drug discovery.

Publications

Targeting human papillomavirus genome replication for antiviral drug discovery.

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