Work package 3:  Molecular Research & Therapy development

IP Shanghai, HKU-PRC, IP-Korea

The main goals of WP3 are:

Research Area 1: Dissection of viral and host factor interaction and pathogenesis of viral respiratory diseases.
Despite their importance as pathogens, little is known about cellular factors that regulate infection of SARS CoV and the highly pathogenic avian influenza (HPAI) H5N1.  The main goal of this research area is to identify and characterize cellular factors able to enhance or restrict early (entry) and late (assembly/budding) stages of viral infection that may represent novel targets for future anti-viral therapy.

One approach has been to use a large-scale yeast two-hybrid screening to look for cellular factors that interact with SARS-CoV Spike, E and M envelope protein CT.  This strategy will be also applied to define the cellular interactome of HPAI H5, M1 and M2 structural proteins.  An alternative approach will rely on the siRNA genome-wide screening to characterize enhancing and restricting cellular factors of H5N1 viral entry.

Research area 2: Development a novel HA-based subunit vaccine strategy which will rapidly adapt antigenic determinants from a new pandemic flu strain.
Currently, two classes of vaccines are licensed for inter-pandemic influenza in the US: parentally delivered inactivated virus vaccines and a live attenuated vaccine delivered as a nasal spray.  They both require several months for mass production and it may be very difficult to develop enough new vaccine from a pandemic virus strain within a reasonable time frame to contain the disease.  Therefore, a vaccine strategy that can quickly produce enough effective immunogen against a pandemic strain will be advantageous.  Since all the five major antigenic determinants as well as the receptor binding site locate within a globular region of HA1, engrafting the cDNA sequence corresponding to this HA segment from a new pandemic strain into a prototype HA gene cassette will result in a new immunogen.  Experiments are under way to test this hypothesis at IP-Shanghai.  We believe that this vaccine strategy, if successful, will allow enough new immunogen against a pandemic flu strain to be produced in 3 to 4 month’s period of time so that many lives will be saved and the flu pandemic will be alleviated.

Research area 3: Identification of novel targets and drugs to treat Influenza
Influenza Drug Discovery Research Project at IP-Korea utilizes a plasmid-based screen using live cells that has the advantage of allowing the identification of both cis- and trans-acting signals involved in influenza virus transcription and replication as potential targets.

The high throughput visual screen has already been validated for the identification of novel inhibitors of HIV replication.  At the same time, HKU-PRC is carrying out in collaboration with the SIMM (Shanghai Institute of Materia Medica) a high-throughput screening of chemical library that includes compounds from TCM to search for inhibitors of H5 entry.