Molluscum contagiosum (MC) is a skin disease caused by the poxvirus molluscum contagiosum virus (MCV). MC presents as skin lesions that can last from months to years before resolving. MC lesions occur in children, adults and immunosuppressed individuals and are restricted strictly to the skin. MCV is transmitted by direct skin-to-skin contact, sexual contact, auto-inoculation from scratching lesions and by indirect inoculation from contaminated fomites. The lesions can be painful following treatments intended to reduce spread. The lesions are also psychologically distressful, even more so when they result in scarring. MC occurs in 2-10% of the worldwide population and in the USA, it constitutes about 1% of all diagnosed skin disorders, and in children it approaches 5%. Significantly, in immunocompromised individuals, this infectious disease can be both severe and protracted. Between 5% and 18% of HIV patients have MC. Often, severe MC disease in AIDS patients begins to resolve while on highly active antiretroviral therapy (HAART). However, there have been documented cases of MC lesions developing soon after starting HAART, suggesting that immune reconstitution inflammatory syndrome (IRIS) might be playing a role in there-emergence of MCV.
The current treatments for MC usually employ physical therapy or chemical agents, which are not uniformly effective or safe, and often fail to completely eliminate lesions and may result in scaring. In addition, the broad-spectrum antiviral drug cidofovir, a dCMP analogue, has been used effectively as topical or intravenous medication for MC in immunocompromised patients, but with side effects including inflammation, erosion and pain for topical treatment and potential nephrotoxicity for systemic application. To date, there is not a single antiviral therapeutic that is licensed for the specific treatment of MC. The development of such an effective and safe treatment has been hampered mainly by the inability of MCV to propagate in culture.
Processivity factors (PFs) are attractive antiviral therapeutic targets. The function of PFs is to tether DNA polymerases (Pol) to the template to enable synthesis of extended strands. PFs are specific for theircognate DNA Pol and are absolutely essential for DNA synthesis. As a case in point, Kaposi's sarcoma herpes virus Pol (Pol-8) alone incorporates only three nucleotides, whereas in the presence of its PF, PF-8, it is able to incorporate many thousands of nucleotides. All DNA Pols from phage to human function with a single cognate PF. However, the prototypic poxvirus, vaccinia virus (VV) is somewhat unusual in that a heterodimer comprising the A20 and D4 viral proteins constitutes the functional PF. D4, which can also function as a uracil-DNA glycosylase repair enzyme, binds to its PF partner A20 but not to E9 Pol. A20 on the other hand, binds to both E9 and D4, suggesting that it serves, in part, as a bridge that indirectly connects D4 to E9. Therefore, effective therapeutics are needed for inhibiting, treating, or abrogating a molluscum contagiosum virus infection.
USPTO Backgrounds
USPTO Backgrounds