Project Details
Projekt
Glycosaminoglycan-papillomavirus interactions: From structure to function and inhibition
Applicant
Professor Dr. Mario Schelhaas
Subject Area
Virology
Term
from 2016 to 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 269564371
Human papillomaviruses (HPV) are a large family of non-enveloped DNA tumor viruses. Of those, HPV16 is the leading cause for a variety of anogenital tumors including cervical cancer. For entry into host cells, HPV16 initially binds to heparan sulfate proteoglycans (HSPGs). Recently, our research demonstrated that the initial interaction of HPV16 capsids with the glycosaminoglycan (GAG) chains of HSPGs is sufficient to induce a conformational change. This facilitates further structural alterations in the virus particle resulting in receptor switching and preparing the particle for uncoating, i.e. the release of the viral genome from the capsid structure (Cerqueira et al., 2013; Cerqueira et al., 2015). This structural activation of the virus appears to be critically dependent on a high sulfation content, on the sulfation pattern, on a certain carbohydrate backbone, and on the lengths of the GAG chain. This observation raises the interesting possibility that the tropism of different HPV types for mucosal vs. skin epithelia depends on a tissue-dependent sulfation patterning of GAGs.In this project, we aim to elucidate the structural prerequisites and consequences of GAG-HPV interactions. For this, we will use an established repertoire of cell-based assays in combination with structural biology approaches within the Forschergruppe to define the structural constraints of the GAG and HPV capsids for binding, structural activation, and inhibitory potential. On the one hand, we will probe the variety of evolutionary diverse HPV types and HS glycans to elucidate common themes and specific differences for this interaction. On the other hand, we will define the ideal GAG structure to cause structural activation of HPV16, as well as the molecular details of the conformational change. The repertoire of methods used in this study capitalizes on the interdisciplinary approach of the Forschergruppe and includes but is not limited to cell-based assays, mass spectrometry, nuclear magnetic resonance studies, and the use of precision glycomimetic polymers. Overall, we expect to identify structural and functional consequences of HS-HPV capsid interactions that will allow us to propose a comprehensive model of HS-dependent entry, which, in turn, could be used to develop preventative anti-HPV compounds.
DFG Programme
Research Units
