Molecular Targets for Antiviral Agents

There are a number of virus-specific processes within the virus replicative cycle or virus-infected cell that have proven to be attractive targets for chemotherapeutic intervention, i.e., virus adsorption and entry into the cells, reverse (RNA 3 DNA) transcription, viral DNA polymerization, and cellular enzymatic reactions that are associated with viral DNA and RNA synthesis and viral mRNA maturation (i.e., methylation). A variety of chemotherapeutic agents, both nucleoside (and nucleotide) and non-nucleoside entities, have been identified that specifically interact with these viral targets, that selectively inhibit virus replication, and that are either used or considered for clinical use in the treatment of virus infections in humans. Their indications encompass virtually all major human viral pathogens, including human immunodeficiency virus (HIV), hepatitis B virus (HBV), herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), human papilloma virus (HPV), orthomyxoviruses (influenza A and B), paramyxoviruses [e.g., respiratory syncytial virus (RSV)] and hemorrhagic fever viruses (such as Ebola virus). For many years virus diseases have been considered as intractable to selective antiviral chemotherapy because the replicative cycle of the virus was assumed to be too closely interwoven with normal cell metabolism so that any attempt to suppress virus reproduction would be doomed to kill (or severely harm) the uninfected cell as well. With the elucidation of virus-specific events as targets for chemotherapeutic attack and the advent of a number of specific antiviral agents, it has become increasingly clear that a selective chemotherapy of virus infections can be achieved and that virus reproduction can be suppressed without deleterious effects on the host. There are currently 30 antiviral drugs that have been officially approved for the treatment of virus infections (De Clercq, 2001a): zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, nevirapine, delavirdine, efavirenz, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, and lopinavir for the treatment of human immunodeficiency virus (HIV) infections; lamivudine also for the treatment of hepatitis B virus (HBV) infections; acyclovir, valaciclovir, penciclovir, famciclovir, idoxuridine, trifluridine, and brivudin for the treatment of herpes simplex virus (HSV) and/or varicella-zoster virus (VZV) infections; ganciclovir, foscarnet, cidofovir, and fomivirsen for the treatment of cytomegalovirus (CMV) infections; ribavirin for the treatment of respiratory syncytial virus (RSV) infections and, in combination with interferon-a, for the treatment of hepatitis C virus (HCV) infections; amantadine and rimantadine for the treatment of influenza A virus infections; and finally, the neuraminidase inhibitors zanamivir and oseltamivir for the treatment of influenza A and B virus infections. Several other compounds, among which are adefovir dipivoxil and tenofovir disoproxil, are momentarily in advanced phase III Prof. Erik De Clercq holds the Professor P. De Somer Chair of Microbiology at the Katholieke Universiteit Leuven School of Medicine. ABBREVIATIONS: HIV, human immunodeficiency virus; HBV, hepatitis B virus; HSV, herpes simplex virus; VZV, varicella-zoster virus; CMV, cytomegalovirus; HPV, human papilloma virus; RSV, respiratory syncytial virus; HCV, hepatitis C virus; IMP, inosine 59-monophosphate; SAH, S-adenosylhomocysteine; RT, reverse transcriptase; NRTI, nucleoside (type of) reverse transcriptase inhibitor; NNRTI, non-nucleoside (type of) reverse transcriptase inhibitor; PVAS, polyvinylalcohol sulfate; PVS, polyvinylsulfonate; TM, transmembrane; M-tropic, macrophage tropic; T-tropic, T-cell tropic; AIDS, acquired immune deficiency syndrome; FIV, feline immunodeficiency virus; SIV, simian immunodeficiency virus; dNTP, deoxynucleoside-59-triphosphate; ddN, 29,39-dideoxynucleoside; d4T, didehydrodideoxythymidine; 3TC, 39-thiadideoxycytidine; DAPD, 2,6-diaminopurine dioxolane; AZT, azidothymidine; NDP, nucleoside 59-diphosphate; MP, monophosphate; TP, triphosphate; HEPT, 1-(2hydroxyethoxymethyl)-6-(phenylthio)thymine; TIBO, tetrahydroimidazo-[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and -thione; BVDU, brivudin; TK, thymidine kinase; EICAR, 5-ethynyl-1-b-D-ribofuranosylimidazole-4-carboxamide; SAM, S-adenosylmethionine; ddI, dideoxyinosine; ddC, dideoxycytidine; ABC, abacavir; (2)-FTC, emtricitabine; (S)-DHPA, (S)-9-(2,3-dihydroxypropyl)adenine. 0022-3565/01/2971-1–10$3.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 297, No. 1 Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics 900052/899393 JPET 297:1–10, 2001 Printed in U.S.A. 1 at A PE T Jornals on A uust 0, 2017 jpet.asjournals.org D ow nladed from clinical trials for the treatment of HBV and HIV infections, respectively. The viral replication cycle can be roughly divided into 10 steps: virus-cell adsorption (binding, attachment), virus-cell fusion (entry, penetration), uncoating (decapsidation), early transcription, early translation, replication of the viral genome, late transcription, late translation, virus assembly, and release. HIV (Fig. 1) follows this general strategy, albeit with some modifications: early transcription (step 4) is replaced by reverse transcription, early translation (step 5) is replaced by integration, and the final steps (assembly and release) occur concurrently as a process that has been dubbed “budding” and that is followed by maturation. All these steps could be envisaged as targets for chemotherapeutic intervention (De Clercq, 2000a). In addition to these virus-specific events, there are a number of host enzymes and processes that are innately involved with viral DNA, RNA, and/or (glyco)protein syntheses. Also, these processes [i.e., inosine 59-monophosphate (IMP) dehydrogenase, S-adenosylhomocysteine (SAH) hydrolase, orotidine 59-monophosphate decarboxylase, CTP synthetase, glycosylation pathways, etc.] may be considered as targets for antiviral agents (De Clercq, 1997). Of all the potential targets for antiviral chemotherapy, I have selected the following eight to be further addressed in this overview (Table 1): 1) virus adsorption as the target for polyanionic substances that inhibit the replication of HIV and other enveloped viruses; 2) virus receptors and co-receptors as the target for antagonists such as the CXCR4 antagonists that block cell entry of T-tropic (X4) HIV strains; 3) HIV reverse transcriptase (RT) as the target for the nucleoside type of reverse transcriptase inhibitors (NRTIs); 4) a second (allosteric) site at HIV-1 RT as the target for the non-nucleoside type of reverse transcriptase inhibitors (NNRTIs); 5) herpesvirus DNA polymerase as the target for a series of acyclic guanosine analogs and 5-substituted 29deoxyuridines that are effective against HSV and VZV (following their phosphorylation by the virus-encoded thymidine kinase); 6) viral DNA polymerase (and reverse transcriptase) as the target for the acyclic nucleoside phosphonates cidofovir, adefovir, and tenofovir; 7) IMP dehydrogenase as a cellular target for the broad-spectrum antiviral activity of a number of IMP dehydrogenase inhibitors; and 8) SAH hydrolase as another cellular target for the activity of adenosine analogs against negatively stranded RNA viruses (including, among others, Ebola virus). The molecular targets, mechanisms of action, antiviral activity spectra, and clinical applications of these eight classes of antiviral compounds are schematically reviewed in Table 1, and chemical structures for representative prototype compounds are given in Fig. 2. 1. Anionic Polymers Targeted at the Viral Glycoproteins Various polyanionic substances have been described to block HIV replication through interference with virus adsorption (binding) to the cell surface, e.g., polysulfates [such as dextran sulfate, dextrin sulfate, and polyvinylalcohol sulfate (PVAS) (Fig. 2)], polysulfonates [such as suramin (the first compound ever to be identified as an inhibitor of HIV replication) and polyvinylsulfonate (PVS) (Fig. 2)], polycarboxylates [such as those equipped with the cosalane pharmacophore (Cushman et al., 1999)], and polyoxometalates [heteropolytungstates containing a single, double, or triple Keggin or single or double Dawson type of structure (Witvrouw et al., 2000b)]. All these polyanionic substances can be assumed to exert their anti-HIV activity by shielding off the positively charged amino acid (lysine and arginine) residues on the V3 loop of the viral envelope glycoprotein gp120 (Fig. 3A), thus preventing the interaction of gp120 with its cellular receptor CD4. Polyanionic (e.g., polysulfonate) dendrimers can inhibit HIV replication by interfering with both virus adsorption and later steps (reverse transcriptase/integrase) in the virus replicative cycle (Witvrouw et al., 2000a). However, the fact that resistance selected upon passaging the virus in the presence of these compounds was associated with mutations in the envelope glycoprotein gp120 (and not the reverse transcriptase or integrase) points to the gp120 as the principal target Fig. 1. Replicative cycle of HIV. 1. Adsorption. 2. Fusion. 3. Uncoating. 4. Reverse transcription. 5. Integration. 6. Replication. 7. Transcription. 8. Translation. 9. Budding. 10. Maturation. 2 De Clercq at A PE T Jornals on A uust 0, 2017 jpet.asjournals.org D ow nladed from