Innovative drugs for the treatment of HIV and HCV infections
AIDS is a pandemic disease that caused in the 2003 more than 3 million deaths, particularly in Sub-Saharian Africa. WHO reports that more than 5 million contracted the infection in the 2003. Although this disease still remains a major social problem in several countries and a definitive cure is not currently available, in the last ten years impressive progress has been made in the treatment of AIDS infected patients. The human immunodeficiency virus (HIV) produces a progressive immunosuppression by destruction of CD4+ T lymphocytes and macrophages, resulting in opportunistic infections, neurological and neoplastic diseases, and death. Among the viral metabolic processes which have been identified in the HIV-1 life cycle for therapeutic intervention, the reverse transcription has been found one of the most attractive ones. Reverse Transcriptase (RT) is a heterodimeric (p51 and p66 subunits) and multifunctional enzyme. Recently, a class of inhibitors targeted to the viral RT, the so called non-nucleoside RT inhibitors (NNRTIs), have gained a definitive place in the treatment of HIV-1 infections along with NRTIs and PIs. First-generation NNRTIs, such as nevirapine, were identified by extensive random screening of different molecules. However, given their very similar mode of action and their unique binding site in the RT enzyme, the occurrence of just a few single aminoacid substitutions in the RT gene can confere resistance to most of the first-generation NNRTIs such as nevirapine. The rationally designed Efavirenz is the prototype of the second generation NNRTIs and shows improved potency against the wild type enzyme and several resistant forms. However the single K103N mutation can still confer cross-resistance to most, if not all, of the members of this subclass. Moreover, NNRTIs are characterized by less severe adverse effects than NRTIs or PIs. Several factors may restrict the selection of antiviral drugs to be used in the combination therapy, such as drug compatibilities, adverse side effects and cross-resistance. Therefore, the development of novel NNRTIs with improved pharmacological, pharmacokinetic and drug resistance mutation profiles, is critical for a more successful application of NNRTIs in combination therapy. Hepatitis C virus (HCV) infection is an emerging global epidemic and no effective cure is available to date. Due to the infection the patients can develop a chronic hepatitis, liver cirrhosis and hepatocarcinoma. The causative agent of hepatitis C, HCV, was identified in 1989 as a flavivirus with a linear genome of approximately 9.6 kb. The genome contains a single open reading frame (ORF) encoding a single polyprotein, that is processed by both virus-encoded and host cellular protease into structural and non-structural (NS) proteins. Among the NS proteins are the protease/helicase NS3 and the RNA-dependent RNA polymerase NS5B. Due to their essential role in viral replication, these two enzymes are considered promising targets for antiviral chemotherapy. The NS3 protein is a multifunctional enzyme with serine-protease and NTPase/helicase activities, and it is implicated both in the processing of the viral polyprotein and in the duplication of the genome of HCV. The helicase activity of NS3 shows a broad substrate specificity, being able to unwind DNA/DNA and RNA/RNA homoduplexes, as well as RNA/DNA heteroduplexes. This peculiar lack of substrate specificity for both the NS3 NTPase and helicase activities, makes the identification of a specific inhibitor a challenging task. However, our recent discovery that, depending on the introduced modifications, similar skeletons can generate either selective anti-HIV or HCV enzyme inhibitors, and the definition of the critical physical-chemical parameters responsible for specificity between the two virus enzyme systems, may pave the way to the rational design of a bi-functional antiviral drug, able to target both viruses simultaneously. This sort of "magic bullet" would have a great impact on the treatment of HIV/HCV co-infections. Indeed, from an epidemiological point of view, the spatial distributions of HCV- and HIV-infected people overlap, with the highest incidence of cases in the third-world countries. As already mentioned, treating HCV infections is a difficult task per se, but it becomes tremendously challenging in the settings of anti-HIV chemotherapy such as HAART, due to the cumulative effects of adverse drug-drug metabolic interactions and toxicity. The possibility to treat both infections with a single drug will undoubtedly represent an enormous advantage. NatSynDrugs results just demonstrate that such an approach might be possible.