Antiviral Strategies: Active Substances and Vaccines

Approved anti-viral drugs with a direct effect mostly block the function of virus-specific enzymes that play an essential role in virus replication. Particularly in the case of highly mutating RNA viruses, agents against different viral targets are combined to increase the resistance barrier and avoid loss of therapeutic efficacy. In recent years, the development of inhibitors of viral proteases and polymerases has been particularly successful, with numerous approved agents. SARS-CoV-2 has a RNA-dependent RNA polymerase as well as two proteases, which are essential for the processing of its polyprotein into the functional protein segments and whose structure has been elucidated, partly with the involvement of scientists from Braunschweig, Germany. Structure-based approaches, such as in silico screening and crystallography, will be used and combined with high-throughput enzymatic assays and cellular antiviral assays to develop tailored drugs against these important viral targets. These include drug discovery and development against the active sites of the respective enzymes as well as the blocking of crucial protein-protein interactions and the tailored development of nucleoside polymerase inhibitors.

Viruses cannot replicate without a host cell and depend on the use of cellular cofactors. Hereby, viruses with comparatively low relatedness use the same cellular factors, so that such host factors emerge as attractive targets for the development of drugs with a broad antiviral spectrum of activity. Well-known examples include inhibitors of cellular kinases already in clinical use, which are important for viral replication, and inhibitors of cellular proteins that play an essential role in the folding of protein complexes, such as cyclophilin inhibitors (non-immunosuppressive cyclosporins). COFONI supports basic research on the structure and function of cellular factors in the context of coronavirus replication. Here, a particular focus is on the identification and characterisation of host factors used by different coronaviruses and also by viruses of other families. The aim is to elucidate viral interactions with these factors and to develop strategies to specifically disrupt this interaction.

Antibodies represent a unique and highly adaptive option for the development of tailored therapeutics. Natural healing of viral infections or effective protection against reinfection is critically supported by highly potent virus-neutralising antibodies. The specific development of therapeutic antibodies uses immune cell libraries from convalescent patients and utilises different selection methods (e.g., single cell sequencing, phage display) to identify effective antibodies. COFONI is funding preclinical development of human or humanised antibodies in appropriate complex primary cell models and animal models. Also, COFONI supports is the development of new antibody screening methods, the targeted optimisation of antibody effector functions using structure-based approaches or through modification of fragment crystallisable regions (Fc regions) as well as the humanisation of highly effective antibodies from non-human antibody libraries.

In the area of vaccines, there is currently an increased focus on the development of vector- and RNA-based vaccine candidates, as these can be produced fast and they already made decisive contributions to combating the SARS-CoV-2 pandemic. Funding is provided for the preclinical development and validation of different vaccination strategies (vectors, nucleic acids, proteins and their combinations) in predictive animal models. This also includes the testing of innovative computational methods for the development of optimised antigens for inducing broadly protective anti-coronavirus immunity. Also in the focus of this funding measure are investigations on the mechanisms of vaccine-induced protection or possible immune enhancement processes, which could cause complicated courses of infection in case of viral reinfection.

In the context of the current outbreak, COFONI partners have contributed significantly to the fight against the SARS-CoV-2 pandemic. In terms of a rapid pandemic response in the field of antiviral agents and being funded by the state of Lower Saxony and the German Center for Infection Research (DZIF), the HZI has focused significant parts of its active substances research on the development of broad-spectrum coronavirus agents. A screening campaign of small-molecule drugs against coronaviruses was directly initiated by the rapid upgrading of S3 capacities at the HZI and the MHH as well as by the immediate provision of proprietary active substances banks of the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), the HZI as well as the MHH. Due to an international cooperation of TWINCORE with the Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology (Jupiter, Florida, USA), the world's largest collection of approved active substances or molecules was also included in the screening. Access to the EU OPENSCREEN library is also available.

The interdisciplinary research team at the HZI (Professor Thomas Pietschmann, Professor Ulrich Kalinke, Professor Mark Brönstrup, Professor Ursula Bilitewski, Professor Anna Hirsch) has profiled more than 45,000 compounds. The expansion of the S3 capacity at the HZI allows the testing of hundreds of compounds for SARS-CoV-2 antiviral activity on a weekly basis.

Due to the HZI's leadership in active substances research of the DZIF and its dedicating large parts of its infection research program exclusively to substance research, the HZI plays a key role in academic anti-infective research in Germany. Within the framework of this alliance, this role is further strengthened by TWINCORE's contributions to active substances research in the field of RNA viruses and by MHH's coordination of the DZIF translational infrastructure for antiviral agents, so that the alliance offers excellent conditions for active substances development.

At the same time, the anchoring of the MHH in the DZIF has led to scientists from the MHH and the TiHo working together to preclinically evaluate DZIF-funded vaccine candidates in animal models.

COFONI partners already achieved important scientific successes in the field of anti-infective strategies in the early stages of the SARS-CoV-2  pandemic. For example, Professor Pöhlmann and colleagues (DPZ Göttingen) have elucidated essential aspects of SARS-CoV-2 cell entry, identified ACE2 as a receptor, and developed an important antibody neutralisation assay. Researchers at the TiHo have identified human monoclonal antibodies that neutralise not only SARS-CoV-2 but also SARS-CoV-1. Professor Dirk Görlich and Dr. Volker Cordes at the Max Planck Institute for Multidisciplinary Sciences in Göttingen are producing therapeutic SARS-CoV-2 nanobodies from alpacas. In contrast to antibodies, nanobodies consist of only one polypeptide chain, which offers multiple advantages in production and handling. In collaboration with partners from TU-Braunschweig and the companies YUMAB GmbH, and CORAT Therapeutics GmbH, the HZI (Professor Luka Cicin-Sain) has identified several antibodies with strong antiviral activity. The most promising candidate COR-101 is in clinical development. Finally, HZI scientists have contributed to the establishment of a new lead structure against the SARS-CoV-2 main protease, and under the leadership of scientists from Göttingen, the structure of the viral RNA polymerase was elucidated. Professor Reinhold Förster was able to show that the reappearance of effector T cells in the blood is associated with reconvalescence of the patients.

Through these scientific successes in identifying and characterizing critical therapeutic targets as well as essential capacity building and linkage to the DZIF national network, the integrating impact of the COFONI research network creates particular opportunities for the development of active agents and vaccines against coronaviruses.