The research performed in the last years has provided

a better understanding on the mechanisms of antitumor efficacy of ANPs. Although comparative studies selleck kinase inhibitor between CDV and ANPs of the PME series (such as PMEG) are missing, their action on cellular DNA polymerization appeared to be different, PMEG having a higher affinity for cellular DNA polymerases than CDV. An important difference between both drugs is the ability of PMEG to cause chain termination of viral DNA synthesis in contrast to CDV that can be incorporated. Although both PMEG and CDV can cause DNA damage, they may differ in the type of damage induced. In the case of CDV, it appeared that the drug is able to induce double-stranded DNA damage and that only normal cells are capable of activating a DNA damage response and repair the damage via homologous recombination (considered as a very faithful mechanism of DNA repair). On the other hand, it appears that CDV is able to trigger several signalling pathways in tumor cells, both HPV-positive and HPV-negative cells, such as Rho GTPase signalling and acute phase response that may also contribute to its antitumor efficacy and selectivity. There is an unmet need for effective anti-HPV treatments for existing infections and for patients that do not receive the prophylactic

vaccination. Also, no FDA-approved treatments exist to manage human PyV infections. The use of cidofovir derivatives such as CMX001 (with substantially improved oral bioavailability and Forskolin reduced toxicity

compared to CDV) and HPMP-5-azaC (with in vitro and in vivo antiproliferative effects equivalent as those described for CDV) deserve further evaluation. Also, the use of formulations of CDV should be envisaged in order to use lower drug levels and enhance efficacy. A recent study has shown that formulation of CDV improved the anti-papillomavirus activity of topical CDV treatments in the CRPV/rabbit model ( Christensen et al., 2014). Importantly, CDV was suggested to affect the LT-ag of PyV, indicating that the helicase activity associated with the LT-ag may be the target of CDV. Although there is no overall homology among the PyV and PV genomes, the helicase motif of PV E1 protein, SPTLC1 a domain stretching about 230 amino acids, has some sequence similarity with the SV40 LT-ag (de Villiers et al., 2004). Furthermore, a comparison of the active s ite from SV40 LT-ag and HPV E1 proteins shows high similarities (Fig. 14A and B). The lysine finger is conserved in the LT-ag and the HPV E1 proteins and, in addition, a number of aspartates, asparagines and threonines are conserved in the active site of both types of proteins. Structural similarities between the LT-ag and the BPV E1 protein have also been described (Topalis et al., 2013).