Hantaviruses are emerging viruses of the Bunyaviridae family that can cause severe human disease. The prototypic Hantaan virus is responsible for thousands of cases of severe hemorrhagic fever with renal syndrome in Asia and the hantaviruses Sin Nombre virus and Andes have emerged in the Americas as causative agents of hantavirus cardiopulmonary syndrome reaching 40% fatality rate. In Europe, hantaviruses represent the most important emerging viruses, including Puumala virus and Dobrava virus that cause a renal syndrome with sometimes severe complications. There is currently no licensed vaccine against hantaviruses and therapeutic options are restricted. The development of novel anti-viral therapeutics against hantaviruses is therefore of high priority.
In a collaborative study with Dr. Olivier Engler, head of the Virology Group of the Spiez Laboratory we aim at the development of novel therapeutics against human pathogenic hantaviruses. The Spiez Laboratory is an internationally recognized center of civil protection specialized in work with Category A, B, and C Select Agents equipped with state-of-the-art high containment laboratories of biosafety levels (BSL)-3 and 4 and a national reference center for highly pathogenic microbes. In our project, we try to target different steps of the hantavirus lifecycle for therapeutic intervention.
Hantaviruses are enveloped viruses whose genome consists of tree RNA segments in negative-strand orientation as shown below. A small genomic RNA segment (S) encodes the viral nucleocapsid protein (N), a medium (M) segment the precursor of the envelope glycoprotein, and a large segment (L) that codes for the viral RNA-dependent RNA polymerase. Hantavirus N and L are crucial to form the viral replication/transcription complex. Based on its crucial role and structural conservation, L represents a promising drug target. Undertaking a small molecule screening approach, we seek to identify specific inhibitors of the hantavirus L polymerase. Candidate inhibitors will then be evaluated for their anti-viral potency against authentic hantaviruses in the high-containment facility of the Spiez Laboratory.
Hantavirus particle and genome structure: (A) Schematic representation of the hantavirus virion. The outer part of the hantavirus is composed by the lipid envelope decorated with Gc and Gn glycoproteins. The particle contains three segments of viral RNA (vRNA): the small (S), the medium (M) and the large (L) open reading frames (ORFs). These are encapsidated by the nucleoprotein (N). The RNA-dependent RNA polymerase (RdRp) is responsible for the replication and the transcription of the viral genome. (B) The S, M and L segments of hantavirus genome code for nucleoprotein (N), Gn and Gc glycoproteins and RNA-dependent RNA polymerase (L), respectively. Red regions represent non-coding regions (NCRs) that flank ORFs symbolized by blue regions. In parenthesis the sizes of the segments are shown.
Collaborators: Prof. Pierre-Yves Lozach (University of Heidelberg, Germany), Dr. Nicole Tischler, (Molecular Virology Laboratory, Fundación Ciencia & Vida, Santiago, Chile).
Funding: Federal Office of Civil Protection project 353004328 (Engler). Collaborative project “Novel Strategies to Combat Human Pathogenic Hantaviruses”