Current Drug Targets - Infectious Disorders - Current Issue

This article summarizes key aspects of progress made during 2004 toward the design, discovery and development of antiviral agents for clinical use. Important developments in the identification, characterization and clinical utility of inhibitors of human immunodeficiency virus; the hepatitis viruses, hepatitis B, hepatitis C; the herpes family of viruses, herpes simplex viruses 1 and 2, varicella zoster virus, Epstein-Barr virus and human cytomegalovirus; the respiratory viruses, influenza, respiratory syncytial virus, human metapneumovirus, picornaviruses, measles and the severe acute respiratory syndrome coronavirus; human papilloma virus; rotavirus; Ebola virus and West Nile virus, are reviewed.

The enzyme neuraminidase (NA) is an attractive target for antiviral strategy because of its essential role in the pathogenicity of many respiratory viruses. NA removes sialic acid from the surface of infected cells and virus particles, thereby preventing viral self-aggregation and promoting efficient viral spread; NA also plays a role in the initial penetration of the mucosal lining of the respiratory tract. Random screening for inhibitors has identified only low-affinity and nonselective viral NA inhibitors. Selective, high-affinity inhibitors of influenza virus neuraminidase, zanamivir and oseltamivir, were developed using computer-aided design techniques on the basis of the three-dimensional structure of the influenza virus NA. These drugs were highly efficient in inhibiting replication of both influenza A and B viruses in vitro and in vivo and were approved for human use in 1999. Subsequently, the same structure-based design approach was used for the rational design of inhibitors of the parainfluenza virus hemagglutinin-neuraminidase (HN). One of these compounds, BCX 2798, effectively inhibited NA activity, cell binding, and growth of parainfluenza viruses in tissue culture and in the lungs of infected mice. Clinical reports indicate high efficiency of NA inhibitors for prophylaxis and treatment of influenza virus infection, good tolerance, and a low rate of emergence of drug-resistant mutants. Future experimental and clinical studies should establish the viability of NA inhibitors for the treatment of other respiratory virus infections.

The emergence and spread of antiparasitic drug resistance pose a severe and increasing public health threat. Failures in prophylaxis or those in treatment with quinolines, hydroxynaphtoquinones, sesquiterpenic lactones, antifolate drugs, arsenic and antimony containing drugs sulfamides induce reemergence of parasitic-related morbidity and mortality. Resistance is often associated with alteration of drug accumulation into parasites, which results from a reduced uptake of the drug, an increased efflux or, a combination of the two processes. Resistance to quinolines, artemisinin derivatives and arsenicals and expression of an active efflux mechanism are more or less correlated in protozoa like Plasmodium spp., Leishmania spp., and Trypanosoma spp. Various parasite candidate genes have been proposed to be involved in drug resistance, each concerned in membrane transport. Genes encoding membrane glycoproteins, orthologue to the Pglycoproteins identified in MDR human cancer cells, have been described in these resistant pathogens in addition to various membrane proteins involved in drug transport. Several compounds have demonstrated, in the past decade, promising capability to reverse the drug resistance in parasite isolates in vitro, in animal models and for human malaria. These drugs belong to different pharmacological classes such as calcium channel blockers, tricyclic antidepressants, antipsychotic calmodulin antagonists, histamine H1-receptor antagonists, analgesic antipyretic drugs, non-steroidal anti-inflammatory drugs, and to different chemical classes such as synthetic surfactants, alkaloids from plants used in traditional medicine, pyrrolidinoaminoalkanes and derivatives, and anthracene derivatives. Here, are summarized the molecular bases of antiparasitic resistance emphasizing recent developments with compounds acting on trans-membrane proteins involved in drug efflux or uptake.

A major problem associated with anti-HIV-1 treatment is rapid emergence of drug-resistant strains. Accordingly, a compelling need is to discover anti-HIV drugs against alternative viral targets in addition to HIV-1 RT, PR, IN and CCR5. One such target is the interaction between HIV Trans-activator of transcription (Tat) protein and Trans Activation Responsive region (TAR) RNA. An arginine-rich motif (ARM) of Tat recognizing both the base sequence and the active conformation of TAR RNA three-base bulge region as well as newly elucidated TAR RNA inactive conformation are important for the specific Tat-TAR interaction. According to the possible binding modes, the inhibitors have been mainly divided into two classes: (1) Compounds binding directly to TAR RNA either to the TAR RNA threebase bulge region alone or to the three-base bulge together with the lower and upper-stem/Loop region. (2) Compounds binding directly to Tat protein with high affinity, thus potently inhibiting HIV-1. They both block Tat trans-activation in the formation of the Tat/TAR complex to exert antiviral activity in primary human cells. Recent researches also focus on the drugs targeting specificity of Tat and TAR by such new assays as capillary electrophoresis and quartz crystal microbalance. Cell-based reporter systems are established for high-throughput screening of novel compounds that interfere with Tat transactivation. The identification of dominant-negative mutants also finds wide application in this field. The Tat-TAR interaction is an important target in efforts to develop anti-HIV gene therapy or potential therapeutic antiviral agents for the treatment of HIV-1 infections.