The design of drugs for HIV and HCV

Key Points Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infect 40 million and 170 million people worldwide, respectively. There is no vaccine for either virus, but drug development is progressing at a rapid pace. Here we review aspects of the medicinal chemistry and history of drug design for HIV and HCV, targeting similar stages in the viral life cycle. At present, 24 drugs have been formally approved for the treatment of HIV infections. They belong to 7 different classes: NRTIs (nucleoside reverse transcriptase inhibitors), NtRTIs (nucleotide reverse transcriptase inhibitors), NNRTIs (non-nucleoside reverse transcriptase inhibitors), protease inhibitors, fusion inhibitors, CRIs (co-receptor inhibitors) and integrase inhibitors (INIs). Current strategies for combating HCV are remarkably reminiscent of those previously pursued for affronting HIV infections. Drug classes that are being developed include inhibitors of the viral protease (aspartyl protease for HIV; serine protease for HCV) and inhibitors of the viral polymerase (RNA-dependent DNA polymerase (reverse transcriptase) for HIV; RNA-dependent RNA polymerase (RNA replicase) for HCV) Cyclophilin inhibitors (such as cyclosporin A analogues) have been found to inhibit both HIV and HCV replication. The ultimate goal in the therapy of any virus is the elimination of the virus from the organism. For HIV, a definitive eradication may not be achievable. For HCV, however, the prospect of a true cure seems much more realistic. As for HIV, any chemotherapeutic approaches to curtail HCV infections are likely to be based on the combination of several drugs interacting with different targets within the viral replicative cycle. Drug development for HIV has been the major driving force in antiviral research. The strategies that are now being pursued for combating hepatitis C virus (HCV) are remarkably reminiscent of those established for HIV. Here, De Clercq reviews aspects of the medicinal chemistry and history of drug design for HIV and HCV. Since the discovery of the human immunodeficiency virus (HIV) in 1983, dramatic progress has been made in the development of novel antiviral drugs. The HIV epidemic fuelled the development of new antiviral drug classes, which are now combined to provide highly active antiretroviral therapies. The need for the treatment of hepatitis C virus (HCV), which was discovered in 1989, has also provided considerable impetus for the development of new classes of antivi