Major aim of the Institute of Molecular Virology, headed by Jan Münch and Frank Kirchhoff, is achieving a better understanding of the molecular properties of HIV-1 and other pathogenic viruses with the ultimate aim to improve preventive and therapeutic strategies. To elucidate how viruses infect cells and reprogram them into effective virus producers, high-resolution imaging techniques are of immense value. Available techniques provide exciting insights into virus-host cell interactions. Despite great recent progress, however, they still have significant limitations. Electron microscopy techniques e.g. provide excellent resolution. However, they require treatments, such as deep freezing or vacuum that might alter or even destroy the biological target structures and preclude the analysis of processes in live cells. Light microscopy techniques have been greatly improved in recent years and allow studying dynamics of virus infection processes. However, their resolution is still limited and does not allow analysing interactions in molecular detail. Our vision within ZQB is to use quantum sensors, such as nanodiamonds, to examine the dynamics of virus entry processes and the cellular response to infection with thus far unprecedented and perhaps ultimately even atomic resolution.
One large family of proteins that is of special interest for our studies are G protein-coupled receptors (GPCRs). These cellular receptors interact with various ligands to activate intracellular signal transduction pathways. They participate in numerous physiological and pathological processes. In addition, they are not only the targets of ~30% of all approved drugs but also the main coreceptors for HIV infection. Important progress has been made in elucidating the structure and function of many GPCRs. Little is known, however, about the dynamics of GPCR action and the conformational changes associated with the binding of various ligands, such as agonists, antagonists or viral envelope glycoproteins, and intracellular signaling. Our goal is to use fluorescent nanodiamonds carrying NV centers (FNDs) and quantum sensing technologies for atomic resolution imaging of signaling and HIV entry mediated by the chemokine receptor CXCR4 in living cells. The long-term vision is to apply quantum sensors to monitor conformational dynamics of proteins in their native environment with atomic resolution in order to get a detailed understanding of GPCR function. This ambitious goal requires close cooperation with the physics and biochemistry groups of ZQB.
Another fundamental question, we would like to address within the framework of ZQB is whether quantum effects might be involved in more biological processes than currently thought? While the key role of electron transfer processes in photosynthesis is well established, it is currently unclear whether they also play a role in GPCR signalling or even viral entry processes. We recently discovered an endogenous inhibitor of CXCR4, a GPCR that plays a key role in many cancers and inflammatory disorders. Optimized forms of this peptide, which was named EPI-X4, not only inhibit HIV-1 infection but also suppress cancer cell migration and exert anti-inflammatory effects. ZQB offers exciting possibilities to study the interaction of CXCR4 with EPI-X4 based inhibitors and subsequent changes in signalling features. The results might not only provide novel insights into the HIV infection process and GPCR signalling but could also promote the design of improved EPI-X4 derivatives for the treatment of cancers and inflammatory diseases. The studies will also greatly benefit from the resources and interactions provided by the CRC 1279 “Exploiting the human peptidome for novel antimicrobial and anticancer agents”.