A drug that is being developed to treat multiple sclerosis (MS) by damping down the immune system may also have the potential to treat viral infections. A study published in the journal, Nature, showed that mice treated with the drug FTY-720 (fingolimod) were able to clear a viral meningitis infection that persisted in untreated mice.
It is, at first sight, surprising that a drug developed to suppress the immune response in MS patients can help to fight a viral infection.
FTY720-P is an agonist of the sphingosine-1-phosphate receptor and causes lymphopenia by preventing egress of lymphocytes from the lymph nodes. The new finding builds on the observation that more easily cleared strains of the virus also cause lymphocytes to become sequestered in lymph nodes. The reason why trapping circulating lymphocytes allows a more robust response to infection is not clear, but may be linked to the fact the lymph nodes are where the immune response is primed. Clearance of the virus does not occur when CD4 T cells are absent at the time of treatment, indicating that the drug is not exerting direct antiviral effects. Some viruses, including HIV, replicate at high levels in lymph nodes and the team plan to test the effect of FTY720 on infection with other viruses.
FTY720 is currently in Phase III clinical trials to test its safety and efficacy as a disease modifying therapy for relapsing-remitting MS.
Influenza A is a major human and animal pathogen with the ability to mutate and cross species: the recent emergence of the H5N1 strain of the Avian Influenza A virus has emphasised the need for new treatments. Between 2003 and 2008 there were 385 confirmed human cases of the avian H5N1 strain (WHO data).
Existing flu treatments such as Tamiflu® and Relenza® target the viral neuraminidase, a highly variable protein on the surface of the virus which can mutate to give viral strains which are resistant to the drugs.
PA-PB1 Complex (pdb id: 3cm8)
Two independent reports (He et.al., Obayashi et.al.) have recently described the crystal structure of the viral RNA polymerase, a protein complex that is essential for viral transcription and replication. The complex contains three proteins, PB1 which has polymerase and endonuclease activities, PB2 which is responsible for binding capped RNA, and PA, the function of which is less clear. Both structures show large fragments of PA bound to a smaller helical fragment of PB1. If it were possible to devise a small molecule that could disrupt this binding, it would likely prevent polymerase activity and viral replication. Although protein-protein interactions are considered to be difficult targets for drug discovery, in this case the binding area is relatively small and offers a potential target for novel anti-influenza drugs.
A drug which failed to reach the market as a treatment for HIV/AIDS has recently been shown to improve the survival of mice infected with West Nile virus, a virus that can cause encephalitis. It is believed that the drug, AMD-3100, acts by allowing T-cells to cross the blood-brain barrier and combat virus infecting the brain.
The drug works by blocking the receptor for the chemokine, CXCR4, and was originally developed to prevent the syncytium-forming variant of HIV using this receptor to gain entry to cells. Clinical trials, however, failed to show robust anti-viral activity.
The CXCR4 receptor and its physiological ligand, SDF-1, are also involved in mobilisation of hematopoietic stem cells into the bloodstream. Genzyme has recently filed applications in the US and Europe for AMD-3100 (Mozobil™, plerixafor) to enhance mobilization of hematopoietic stem cells for collection and subsequent autologous transplantation in patients with lymphoma and multiple myeloma. Because patients receive high-dose chemotherapy, which destroys bone marrow, a stem cell transplant is needed after chemotherapy to replenish blood-forming bone marrow cells. Genzyme has been developing Mozobil since its acquisition of AnorMED in 2006.