Our Approach

Virulence Factors as Drug Targets

Viral Virulence Factors Modulate the Host Immune System

Viral virulence factors include viral proteins and micro RNAs that modulate the immune system of the infected host. The evolution of viruses has commonly equipped them with virulence factors to attenuate the host immune system and thereby facilitate propagation of the virus. Virulence factors influence the severity of the resultant disease in the host. Virulence factors can be defined functionally as genes for which inactivation impairs propagation of a virus in a host organism but not in cell culture. Virulence factors can be acquired forms of host genes known as homologues. Such viral homologues may have evolved with new or different functions to the original host genes. Other virulence factors have no clear homology to host genes and likely evolved independently.

Viral Virulence Factors as a Novel Route to Therapeutics for Autoimmunity and Inflammatory Diseases

VLST is pioneering the commercial exploitation of viral virulence factors to create novel therapeutics for autoimmunity and inflammatory diseases. VLST’s drug development strategy utilizes a proprietary bioinformatics-proteomics platform to identify viral virulence factors and their host targets. We investigate the biologic consequences of the viral protein-host protein interaction and then develop biologics that mimic some or all activities of the virulence factors. We focus on developing potent therapeutics using antibody and Fc fusion proteins directed against cell surface and secreted targets. Intracellular targets identified for viral virulence factors may be suitable for the development of small molecule drugs.

Two hypotheses underlie VLST’s pursuit of viral virulence factors as a route to novel therapeutics for autoimmunity and inflammatory diseases. Firstly, viral virulence factors can be used to identify a key subset of human proteins that are targetable with drugs to modulate the human immune system for therapeutic benefit. Secondly, novel therapeutic strategies can be developed by understanding how viruses modulate the activity of human proteins.

Therapeutic Design Guided by a Viral Virulence Factor

Enbrel® (etanercept), a soluble form of TNFR2 fused to the Fc portion of IgG1, provides the prototypical example of therapeutic design guided by a viral virulence factor. TNFR2 has significant amino acid sequence homology to the T2 protein of a pox virus known as Shope fibroma virus. T2 is a dimeric protein secreted by Shope fibroma virus which neutralizes the proinflammatory cytokine, tumor necrosis factor (TNF) and thereby facilitates viral propagation. The therapeutic design of Enbrel® recapitulates key functional attributes of the T2 protein. Enbrel® is now an Amgen product used for the treatment of multiple inflammatory diseases involving TNF and has worldwide annual sales exceeding $4 billion.