Viruses and the ubiquitin system

The anti-viral drug development program is based on the premise that targeting host proteins essential for virus production (rather then viral proteins) can circumvent the inherent problem facing efficient long-term anti-viral therapy, namely the emergence of drug resistant variants. For production of mature progeny, viruses hijack host biochemical mechanisms. The fundamental role of the ubiquitin system in cellular physiology predicts a critical regulatory function of virus-host interactions. Indeed, recent studies indicate that ubiquitination plays a major role in virus entry, virus expression, virus assembly and resistance to host restriction and evasion from immune surveillance.
E3 ligases determine the substrate specificity of the ubiquitin system. Therefore, inhibition of E3 ligases should facilitate the development of selective anti-viral drugs.

Influenza
Influenza (flu) virus infection is a major public health hazard. Flu virus drug development presents a unique opportunity for targeting host proteins: Toxicity risks that may be associated with long-term inhibition of a host protein, are significantly reduced considering that influenza virus infection is acute and requires treatment for only a very short time period (few days). A further opportunity for anti-flu drug development is the possibility of using inhalation as a route for efficient introduction of an anti-viral drug to the lungs, the major site of the flu infection. Therefore, the objective of the influenza drug discovery & development program is to initially identify an E3 ligase vital for flu virus biogenesis and subsequently, to enhance the drug development process by developing an RNA interference-based drug that is administered via inhalation.
Targeting of evolutionary conserved host virus interaction is likely to facilitate effective anti-viral therapy for a variety of flu strains.

HIV-1
Proteologics carries out two drug discovery projects aimed at developing E3-based anti HIV drugs. The two proprietary E3 anti-viral targets regulate distinct biochemical pathways essential for virus biogenesis.
Initial discoveries published in 2001 in the Proceedings of the National Academy of Sciences (USA) indicate direct involvement of the ubiquitin-proteosome pathway in the late stages of the HIV life cycle. Since the publication of these seminal reports, Proteologics has carried out several target discovery programs aimed at identifying E3 ligases involved in HIV biogenesis. Based on original host-virus interactions research, assisted by proprietary research tools, Proteologics has identified a number of critical E3 ligases. The first anti-viral target, Plenty Of SH3 (POSH), is an ubiquitin E3 ligase that modulates a late stage of virus assembly. Several small molecule inhibitors of POSH that demonstrate significant anti-viral activity in established virus replication systems are in development. Initial results suggest that POSH-based inhibition may have broader anti-viral implications.