Erik De Clercq

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..between Antonín Holý [Institute of Organic Chemistry and Biochemistry (IOCB, Prague, Czech Republic)] and Erik De Clercq (Rega Institute for Medical Research, K.U. Leuven, Belgium) started exactly 30 years ago...

..Other PrEP studies are still ongoing. Available data point to the efficacy and safety of TDF with or without FTC in the prophylaxis of HIV infection (AIDS)...

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..These compounds should be used in drug combination regimens to achieve the highest possible benefit, tolerability and compliance and to diminish the risk of resistance development...

..e. human papilloma viruses, adenoviruses, human herpesvirus type 6, poxviruses, severe acute respiratory syndrome coronavirus and hemorrhagic fever viruses)...

..e. PMPO-DAPy, PMEO-DAPy, HPMPO-DAPy) and cyclic nucleoside phosphonates (i.e. PMDTA, PMDTT, GS9148) have been accredited with an antiviral potency and selectivity similar to those of cidofovir, adefovir and/or tenofovir...

..This review will chart the origins and development of the most important of the antiviral prodrugs to date...

..As has been shown for other viral infections, RNA interference could be a powerful means with which to suppress the replication of avian H5N1...

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..This article reviews agents that have been shown to have activity against influenza A viruses and discusses their therapeutic potential, and also describes emerging strategies for targeting these viruses...

..These compounds are used in various drug combination (some at fixed dose) regimens so as to achieve the highest possible benefit and tolerability, and to diminish the risk of virus-drug resistance development...

..This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, vol. 85, issue 1, 2010...

..e. integrase and reverse transcriptase. These multiple (triple or quadruple) drug combinations should be aimed at once daily dosing...

..e. AMD11070, AMD3465, KRH-3955, T-140, and 4F-benzoyl-TN14003), primarily as potential anti-HIV agents. They are all strong CXCR4 antagonists. Their role in stem cell mobilization remains to be assessed...

..This work, initiated in collaboration with the late Paul A.J. Janssen, eventually led to the identification of rilpivirine as perhaps an "ideal" NNRTI...

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..For other compounds found to be effective against the dengue virus, including geneticin (G418) and FGI-106, the mechanism of action still remains unresolved...

..Combination of several anti-HIV drugs [often referred to as highly active antiretroviral therapy (HAART)] has drastically altered AIDS from an almost uniformly fatal disease to a chronic manageable one...

..The furo[2,3-d]pyrimidin-2(3H)-one is the key structural determinant in the exquisitely potent activity of its derivatives (R = 2-deoxyribosyl; R' = p-pentylphenyl) against VZV (varicella-zoster virus) replication. [structure: see text]...

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..Here, I describe the rationale behind current and future drug-based strategies for combating viral infections...

..The mode of anti-HIV action of the antibiotic aglycon derivatives could be ascribed to inhibition of the viral entry process...

..The particular characteristics of one of the most potent compounds in this series (5-[[3-(4-chlorophenyl)-5-isoxazolyl]methyl]-2-(2,3-difluorophenyl)-5H-imidazo[4,5-c]pyridine or GS-327073), were studied...

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..It appears that drug-resistant mutants arising under the pressure of HPMP derivatives have the lowest levels of neurovirulence...

..e., azapeptidic (atazanavir)) or non-peptidic scaffold (i.e., cyclic urea (mozenavir), 4-hydroxy-2-pyrone (tipranavir)). Non-peptidic PIs may be expected to inhibit HIV mutant strains that have become resistant to peptidomimetic PIs...

..Here, the virus infections for which antiviral therapy is needed and the compounds that are available, or are being developed, for the treatment of these infections are described...

..The plant lectins represent a well-defined class of anti-HIV (microbicidal) drugs with a novel HIV drug resistance profile different from those of other existing anti-HIV drugs...

..Our findings have important implications for the development of new NNRTIs with pronounced activity against a wider range of lentiviruses...

..The potential of BPIP for the treatment of pestivirus and hepacivirus infections is discussed...

..The last class showed the highest activities and selectivities against both polyomaviruses...

..Our results support the development of alkoxyalkyl esters of ANPs as antivirals not only for the treatment of complicated human orf lesions, but also in the therapy and prophylaxis of contagious ecthyma in sheep and goats...

..Our results demonstrate that compounds belonging to the newly synthesized ANPs, in addition to cidofovir, represent promising candidates for the treatment of poxvirus infections...

..The 6-[2-(phosphonomethoxy)alkoxy]-2,4-diaminopyrimidines offer substantial potential for the treatment of a broad range of retro-, hepadna-, herpes-, adeno-, and poxvirus infections...

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..The ATPase activity of 2C, however, remained unaltered in the presence of TBZE-029...

..Co-receptor antagonists such as AMD3100 show promising anti-HIV-2 therapeutic modalities. Both AMD3100 and enfuvirtide could be used for prophylaxis against SHIV89.6...

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..Taken together, it is obvious that the approaches for the treatment of HIV infections in recent years have become both more diverse and more efficient...

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..Integrase-chimeric virus technology confirmed that the integrase mutations are indeed fully responsible for the resistance phenotype of IIIB/S-1360...

..It is concluded that a single drug-binding pocket exists within the finger domain region of the BVDV RdRp that consists of two separate but potentially overlapping binding sites rather than two distinct drug-binding pockets...

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..CONCLUSIONS: Based on their mode of action, which is different from that of clinically approved anti-HIV drugs, PDPs are good candidates for further development into new drugs and to be included in future combination regimens...

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..This review will focus on new compounds that inhibit a specific viral process (viral targets) and on cell-based approaches (cellular targets) that result in selective inhibition of virus replication...

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..Foremost among these newer compounds are adefovir dipivoxil, entecavir and telbivudine...

..They did not inhibit recombinant HIV-1 reverse transcriptase. All compounds were inactive against HIV in thymidine kinase-deficient cells, pointing to the compounds' requirement to release free AZT to afford antiviral efficacy...

..We, therefore, conclude that CMV423 exerts its activity against HHV-6 through inhibition of a cellular process that is critical at early stages of viral replication and that may affect protein tyrosine kinase activity...

..To evaluate the anti-HIV-1 activity of the cyclotriazadisulfonamide CADA against primary isolates in vitro and the combination of CADA with approved anti-HIV drugs for potential synergy...

..As to the replication kinetics of the selected strains, the replication fitness for all strains was lower than that of the wild-type HIV-1 strain...

..Evaluation of a wide variety of pyridine N-oxide derivatives on their inhibitory activity against feline coronavirus (FIPV strain) and human SARS-CoV (Frankfurt strain-1) in cell culture...

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..AMD3451 is the first low-molecular-weight anti-HIV agent with selective HIV coreceptor, CCR5 and CXCR4, interaction...

..We point to potential pitfalls in defining an inhibitor as an authentic integrase inhibitor, and propose new strategies and technologies for the discovery of authentic HIV integration inhibitors...

..Here, we describe the establishment of a novel CD4+ cell line, U87.CD4.CCR5.CXCR4, stably expressing both CCR5 and CXCR4 at the cell surface...

..These findings may have implications when planning clinical studies with valopicitabine...

..The incorporated PMDTA fits very well in the active site pocket of HIV-1 reverse transcriptase...

..8 microM level. At the same time, the bis(thioester) modification was less cytotoxic to uninfected MT-4 cells, with a CC(50) of >224 microM versus 160 microM for the parent compound...

..7 microM and cytostatic at > or =11 microM, while dienoic esters 16a,b showed activity against both varicella-zoster virus (at 10 microM, 16a) and cytomegalovirus (at 10 microM, 16a; 18 microM, 16b)...

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..Moreover, stability studies of the [TSAO-T]-[PFA] conjugates demonstrated that the compounds were stable in PBS whereas some of the conjugates regenerated the parent inhibitors in extracts from CEM cells...

..These results were confirmed by Docking Studies using the program, Glide ligand docking jobs, which suggests hydrogen bonding between amide N-H of Lys 101 and nitrogen of the cyanomethyl and picolyl group...

..We found that 1-benzyl-3-(3,5-dimethylbenzyl)uracil and 1-cyanomethyl-3-(3,5-dimethylbenzyl)-4-thiouracil showed powerful inhibition against HCMV and HIV-1, respectively...

..0023-0.0110 mumol/mL), comparable to that of the reference drugs adefovir and tenofovir, but were devoid of measurable toxicity at 0.3 mumol/mL...

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..The results presented here suggest that compound 10 should be considered as a new lead in the development of antiviral agents...

..The best of these compounds was only 4.6-fold less potent than 3'-azido-3'-deoxythymidine-5'-monophosphate (AZTMP). This study demonstrates the utility of structure-based drug design methods in the search for novel enzyme inhibitors...

..Computational studies were used to delineate the ligand-RT interactions and to probe the binding of the ligands to HIV-1 RT...

..This is the first report on the clinical course of a BMT-associated ACV(r) HSV-1 infection that subsequently developed resistance to foscarnet as well...

..Compound 4 showed inhibition of HIV-1 (EC50 0.45 microg mL-1) and HIV-2 (0.50 microg mL-1), while 11 showed inhibition of HIV-1 (EC50 2.48 microg mL-1, SI = 4)...

..Biological testing shows that our strategy was successful in searching for new structural leads as HIV-1 IN inhibitors...

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..Among the test compounds, zidovudine was found to be the most active. The order of potency was zidovudine > phosphonylmethoxyethoxydiaminopyrimidine = phosphonylmethoxypropyldiaminopurine > tenofovir > or = adefovir > stavudine...

..These models also indicate a preference for hydrophobic compounds to obtain good HIV-1 RT inhibitory activity...

..Some compounds showed moderate activity against both wild-type HSV-1 and HSV-2, as well as against a thymidine kinase deficient strain of HSV-1. These results suggest a novel mode of action for this group of nucleoside analogues...

..Yet, the therapeutic index of compounds 17 and 21 for CMV and VZV approached the tenfold cut-off point. Compounds 8 and 21 exhibited some cytostatic activity against leukemia and melanoma cell lines...

..The chlorine derivative 3 inhibited both HIV-1 and HIV-2 replication in MT-4 cells with IC(50) values of 10.67 microM and of 13.79 microM, respectively...

..Thus, the acridone scaffold, when appropriately functionalized, can yield compounds with selective activity against pestiviruses and related viruses such as the HCV...

..The methyl ester and methoxy substituents on both of the aromatic rings in the parent compound 1 were successfully replaced with metabolically stable moieties with retention of anti-HIV activity and a general decrease in cytotoxicity...

..Consequently, CMX157 represents a second-generation tenofovir analog which may have an improved clinical profile...

..37-29.50 microM, and the IC(50) values for anti-HIV-2 activity fall into the range 23.11-181.07 microM. The results indicated that these compounds are moderately active against HIV-1 and HIV-2...

..Val-Ala-AZT appears to combine chemical stability with good affinity for the hPEPT1 transporter and an improved cytotoxicity/antiretroviral index relative to AZT...

..The computational analysis showed that the N-3 Boc group promotes new interactions in the binding site of the enzyme leading to a good inhibitory activity...

..The most active HIV-2 inhibitor was compound 7i (R1 = benzyl, R2 = 4-t-butyl-benzyl) with an EC50 value of 18.7 microM and SI=15, which may provide a useful lead for further molecular optimization...

..Preliminary structure-activity relationship (SAR) studies revealed that both modulation of the amino function at C(2) and of the alkyl group at C(5) of the pyrimidine ring are crucial for high anti-HIV-1 activity...