Acronimo: MPXV G4-LANDSCAPE

Titolo: Monkeypox: insights into the viral biology and the related G-quadruplex landscape will reveal its host-dependency factors and disclose innovative antiviral targets

Codice Progetto: P2022BLFBL

Responsabile scientifico per il DMM: Prof.ssa Ilaria Frasson
Coordinatore: Università degli Studi di PADOVA - Prof.ssa Ilaria Frasson

Partner-Unità di ricerca: Università degli Studi di Napoli Federico II - Università degli Studi di Pavia

Bando: PRIN 2022 PRIN - Decreto Direttoriale n. 1409 del 14-09-2022
Durata: 30/11/2023 - 29/11/2025 (24 mesi)

Finanziamento progetto: € 238.840,00 – CUP C53D23007400001

 

Abstract del progetto

In July 2022, the WHO declared a public health emergency of international concern regarding monkeypox, the viral disease caused by monkeypox virus (MPXV). With a mortality rate approaching 10%, MPXV needs to be restrained in its diffusion among humans, to protect people with underlying immune deficiencies that are at higher risk of more serious symptoms. Treatment options are based on pain/fever relief, no specific antiviral drug is available. The scale of this outbreak is much larger than the previous ones, due to viral genomic modifications that led to an infectivity rate higher than expected. As well, this outbreak has been fueled by the limited knowledge on the pathogen; its biology and its replication in animal and human hosts have not been elucidated yet. Also, MPXV is the viral prototype of a wider group of Poxviridae viruses widely distributed in the livestock that can spill to the human host. This proposal sprang from the lack of data on MPXV and from the urgent need to define a reliable method that consent the retrieval of viral and host-dependency factors, targetable by FDA approved drugs or usable for drug design. Here, we propose an extensive study on MPXV infection, by employing cutting edge approaches such as i) transcriptomics and metabolomics to understand the effects of the viral infection on the host cells and ii) an innovative ChIP-sequencing method, adaptable to the study of every kind of virus infection, to detect regions containing G-quadruplexes. We set up a research group, made up of three research units (RUs), with complementary expertise in human virology, organic and analytical chemistry and with a common wide expertise in identification, characterization and targeting of nucleic acids secondary structures. In particular, the three RUs have widespread expertise in G-quadruplexes (G4s), non-canonical DNA and RNA structures that the PIs of the proposal have proved to be associated to essential virological and biological functions, such as DNA transcription or replication. The PIs have successfully designed and tested compounds targeting viral or cellular G4s feasible as antimicrobial or antiproliferative agents. Thus, our expertise is intended to: a. assess the MPXV biology and the virus-host interactions; b. detect viral and cellular dependency factors, c. identify innovative antiviral targets and d. screen feasible antiviral compounds from FDA approved drugs and from an in-house library of G4-ligands. A step wise approach, coordinated into three main Activities, subdivided into specific tasks, has been planned: Activity 1 will elucidate the Virus-Host interaction network in different hosts; Activity 2 will convey the G4-landscape and point out innovative antiviral targets, by means of the G4-landscape method, whereas Activity 3 will be focused on the evaluation of antiviral compounds.