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Emiko Urano Sherimay D. Ablan Rebecca Mandt Gary T. Pauly Dina M. Sigano Joel P. Schneider David E. Martin Theodore J. Nitz Carl T. Wild Eric O. Freed 《Antimicrobial agents and chemotherapy》2016,60(1):190-197
Concomitant with the release of human immunodeficiency virus type 1 (HIV-1) particles from the infected cell, the viral protease cleaves the Gag polyprotein precursor at a number of sites to trigger virus maturation. We previously reported that a betulinic acid-derived compound, bevirimat (BVM), blocks HIV-1 maturation by disrupting a late step in protease-mediated Gag processing: the cleavage of the capsid-spacer peptide 1 (CA-SP1) intermediate to mature CA. BVM was shown in multiple clinical trials to be safe and effective in reducing viral loads in HIV-1-infected patients. However, naturally occurring polymorphisms in the SP1 region of Gag (e.g., SP1-V7A) led to a variable response in some BVM-treated patients. The reduced susceptibility of SP1-polymorphic HIV-1 to BVM resulted in the discontinuation of its clinical development. To overcome the loss of BVM activity induced by polymorphisms in SP1, we carried out an extensive medicinal chemistry campaign to develop novel maturation inhibitors. In this study, we focused on alkyl amine derivatives modified at the C-28 position of the BVM scaffold. We identified a set of derivatives that are markedly more potent than BVM against an HIV-1 clade B clone (NL4-3) and show robust antiviral activity against a variant of NL4-3 containing the V7A polymorphism in SP1. One of the most potent of these compounds also strongly inhibited a multiclade panel of primary HIV-1 isolates. These data demonstrate that C-28 alkyl amine derivatives of BVM can, to a large extent, overcome the loss of susceptibility imposed by polymorphisms in SP1. 相似文献
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Alkoxyalkyl Esters of 9-(S)-(3-Hydroxy-2-Phosphonomethoxypropyl) Adenine Are Potent and Selective Inhibitors of Hepatitis B Virus (HBV) Replication In Vitro and in HBV Transgenic Mice In Vivo
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John D. Morrey Brent E. Korba James R. Beadle David L. Wyles Karl Y. Hostetler 《Antimicrobial agents and chemotherapy》2009,53(7):2865-2870
Alkoxyalkyl esters of acyclic nucleoside phosphonates have previously been shown to have increased antiviral activity when they are administered orally in animal models of viral diseases, including lethal infections with vaccinia virus, cowpox virus, ectromelia virus, murine cytomegalovirus, and adenovirus. 9-(S)-(3-Hydroxy-2-phosphonomethoxypropyl)adenine [(S)-HPMPA] was previously shown to have activity against hepatitis B virus (HBV) in vitro. To assess the effect of alkoxyalkyl esterification of (S)-HPMPA, we prepared the hexadecyloxypropyl (HDP), 15-methyl-hexadecyloxypropyl (15M-HDP), and octadecyloxyethyl (ODE) esters and compared their activities with the activity of adefovir dipivoxil in vitro and in vivo. Alkoxyalkyl esters of (S)-HPMPA were 6 to 20 times more active than unmodified (S)-HPMPA on the basis of their 50% effective concentrations in 2.2.15 cells. The increased antiviral activity appeared to be due in part to the increased uptake and conversion of HDP-(S)-HPMPA to HPMPA diphosphate observed in HepG2 cells in vitro. HDP-(S)-HPMPA retained full activity against HBV mutants resistant to lamivudine (L180M, M204V), but cross-resistance to a mutant resistant to adefovir (N236T) was detected. HDP-(S)-HPMPA is orally bioavailable and provides excellent liver exposure to the drug. Oral treatment of HBV transgenic mice with HDP-(S)-HPMPA, 15M-HDP-(S)-HPMPA, and ODE-(S)-HPMPA for 14 days reduced liver HBV DNA levels by roughly 1.5 log units, a response equivalent to that of adefovir dipivoxil.9-(S)-(3-Hydroxy-2-phosphonomethoxypropyl)adenine [(S)-HPMPA] is an acyclic nucleoside phosphonate which Holý and coworkers first reported in 1986 (7, 8, 26). (S)-HPMPA was the first acyclic nucleoside phosphonate, a growing and important class of antiviral compounds which now includes cidofovir, adefovir [9-(2-phosphonomethoxyethyl)adenine], and tenofovir [9-(2-phosphonomethoxypropyl)adenine], which are used for the treatment of cytomegalovirus (CMV), hepatitis B virus (HBV), and human immunodeficiency virus (HIV) infections, respectively (6). In this paper, we report on the synthesis and evaluation of several alkoxyalkyl ester prodrugs of (S)-HPMPA in an attempt to find oral treatments for HBV infection more effective than the currently approved antivirals.(S)-HPMPA is a broad-spectrum antiviral which was shown to inhibit the replication of a wide variety of double-stranded DNA viruses, including orthopoxviruses, herpesviruses, adenoviruses, iridoviruses, and papovaviruses (6). (S)-HPMPA was also reported to be active in vitro against HBV replication in HB611 cells (29) and 2.2.15 cells (11) and to have 50% effective concentrations (EC50s) of 1.15 and 1.5 μM, respectively. Numerous reports have indicated that (S)-HPMPA lacks activity against HIV type 1 (HIV-1) (2, 5, 12). However, alkoxyalkyl esters of (S)-HPMPA, such as hexadecyloxypropyl-(S)-HPMPA [HDP-(S)-HPMPA] and octadecyloxyethyl-(S)-HPMPA [ODE-(S)-HPMPA], exhibit EC50s against HIV-1 in the low nanomolar range, while unmodified (S)-HPMPA is virtually inactive in vitro (13). HDP-(S)-HPMPA exhibits multiple-log increases in antiviral activity in vitro compared with the activity of unmodified (S)-HPMPA against vaccinia virus, cowpox virus, human CMV and murine CMV (3), and adenovirus (10). HDP-(S)-HPMPA is orally bioavailable and is active in vitro against lethal vaccinia virus and cowpox virus infections (24) and against lethal murine CMV infections (25). To assess the effect of alkoxyalkyl esterification of (S)-HPMPA on its in vitro and in vivo anti-HBV activity, we synthesized HDP-(S)-HPMPA, 15-methyl-HDP-(S)-HPMPA [15M-HDP-(S)-HPMPA], and ODE-(S)-HPMPA and evaluated their in vitro activities against HBV replication as well as the cellular uptake and conversion of HDP-(S)-[8-14C]HPMPA to (S)-HPMPA diphosphate (HPMPApp) in HepG2 cells. Using HDP-(S)-[8-14C]HPMPA, we also evaluated the oral pharmacokinetics and the level of drug exposure in the plasma, livers, and spleens of mice. Finally, the oral activities of the HDP, ODE, and 15M-HDP esters of (S)-HPMPA were assessed in HBV transgenic mice (15, 17, 21); and their activities were compared with the in vivo activity of adefovir dipivoxil, a compound licensed for use for the treatment of HBV infection. 相似文献
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Dicaffeoylquinic and Dicaffeoyltartaric Acids Are Selective Inhibitors of Human Immunodeficiency Virus Type 1 Integrase 总被引:8,自引:1,他引:8
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Brenda McDougall Peter J. King Bor Wen Wu Zdenek Hostomsky Manfred G. Reinecke W. Edward Robinson Jr. 《Antimicrobial agents and chemotherapy》1998,42(1):140-146
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Bacterial cytoskeletal proteins are an emerging set of targets for antibiotic development. This paper describes oligochlorophen analogs based on the monomer 4-chloro-2,6-dimethylphenol as antimicrobial agents against Bacillus anthracis. The most potent analogs have a MIC of 160 to 320 nM against B. anthracis and may target the cytoskeletal protein FtsZ. B. anthracis develops resistance to the oligochlorophens at a rate of 4.34 × 10−10 per generation, which is ∼10-fold lower than that of commercial antibiotics used to treat this human pathogen.Bacillus anthracis infections typically are treated by long-term exposure to antibiotics, during which resistance to these compounds may emerge (2, 4, 19). The discovery of new cellular targets and the development of inhibitors of these proteins will play a key role in this clinical tug of war. Bacterial cytoskeletal proteins are attractive targets for antibiotic development, as they are conserved, essential, and play a central role in cell physiology in eubacteria (10, 13, 18). The best-characterized protein in this family arguably is FtsZ, which is a GTPase with structural homology to eukaryotic tubulin (7). This protein assembles into the Z ring at the site of cell division, which forms the scaffold for the divisome and directs the remodeling of the cell wall to produce a daughter cell.A screen for small-molecule inhibitors of FtsZ identified several hits, including 3Z1; we use the nomenclature nZ1, where Z1 corresponds to the zantrin oligomeric structure described by Margalit et al. and n indicates the number of repeating structural units (Fig. (Fig.1)1) (12). 3Z1 inhibits the GTPase activity of recombinant Escherichia coli FtsZ in vitro (12). Several groups previously had described 3Z1 and structurally related compounds as antibiotics (3, 14, 15). Although these compounds have not been explored as clinical therapeutic agents, 2Z1 has been used as a commercial anthelmintic agent, and its 50% lethal dose (LD50) is 1,506 (95% confidence interval [CI], 1,310 to 1,760) and 1,683 (95% CI, 1,402 to 1,986) mg/kg of body weight in male and female rats, respectively (6).Open in a separate windowFIG. 1.Structure of oligochlorophens. Chemical structures of the compounds studied; n indicates the number of p-chlorophenol units.Guided by the observation that 3Z1 inhibited Bacillus cereus with a MIC of ∼0.3 μM, we investigated this compound and structurally related oligomers as antibiotics against B. anthracis. Polyphenols have several characteristics that make them attractive as therapeutic agents: (i) they are nontoxic to humans; (ii) they are consumed in large amounts daily via fruits and vegetables; (iii) they are rapidly absorbed by the lumen of the gut; and (iv) they have been implicated in the prevention of diseases (17). We were particularly interested in exploring these compounds as a test bed for determining the resistance profile of bacteria exposed to inhibitors of the bacterial cytoskeleton. While the development of resistance is unlikely to be a problem with an absolute solution, the treatment of cells with antimicrobials that are designed to disrupt the function of cytoskeletal proteins may reduce the rate at which these events occur (1). 相似文献
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Sam Hopkins Bernard Scorneaux Zhuhui Huang Michael G. Murray Stephen Wring Craig Smitley Richard Harris Frank Erdmann Gunter Fischer Yves Ribeill 《Antimicrobial agents and chemotherapy》2010,54(2):660-672
SCY-635 is a novel nonimmunosuppressive cyclosporine-based analog that exhibits potent suppression of hepatitis C virus (HCV) replication in vitro. SCY-635 inhibited the peptidyl prolyl isomerase activity of cyclophilin A at nanomolar concentrations but showed no detectable inhibition of calcineurin phosphatase activity at concentrations up to 2 μM. Metabolic studies indicated that SCY-635 did not induce the major cytochrome P450 enzymes 1A2, 2B6, and 3A4. SCY-635 was a weak inhibitor and a poor substrate for P-glycoprotein. Functional assays with stimulated Jurkat cells and stimulated human peripheral blood mononuclear cells indicated that SCY-635 is a weaker inhibitor of interleukin-2 secretion than cyclosporine. A series of two-drug combination studies was performed in vitro. SCY-635 exhibited synergistic antiviral activity with alpha interferon 2b and additive antiviral activity with ribavirin. SCY-635 was shown to be orally bioavailable in multiple animal species and produced blood and liver concentrations of parent drug that exceeded the 50% effective dose determined in the bicistronic con1b-derived replicon assay. These results suggest that SCY-635 warrants further investigation as a novel therapeutic agent for the treatment of individuals who are chronically infected with HCV.Hepatitis C virus (HCV) is a member of the Flaviviridae family, which comprises three distinct genera, including the flaviviruses (such as yellow fever virus, dengue virus, West Nile virus, and Japanese encephalitis virus), the pestiviruses (bovine viral diarrhea virus and classical swine fever virus), and the hepaciviruses (of which HCV is the only member) (16). HCV is highly polymorphic, and current taxonomic schemes recognize six major genotypes and several subtypes. Although no strict relationship exists between the genotype and the severity of HCV disease or the clinical outcome, numerous clinical studies indicate that patients who are infected with genotype 1 viruses are less responsive to antiviral therapy than individuals who are infected with genotypes 2 through 6 (10, 11). Chronic infection with HCV now represents a major global health problem, with approximately 170 million people worldwide being infected (26). The current standard of care for chronic hepatitis C virus infection involves treatment for up to 1 year with combination chemotherapy of pegylated alpha interferon coadministered with ribavirin. At this time, there are no approved drugs specifically indicated for the treatment of patients who do not respond to first-line therapy. Complete clearance of the virus is achieved in approximately 50% of all HCV-infected patients who initiate therapy (10, 11), and the response rates are related to viral factors (the genotype and the viral load), as well as multiple host factors (the presence of liver fibrosis, cirrhosis, ethnicity, coinfection with HIV type 1 [HIV-1], alcohol consumption, and metabolic disorders).At this time, the combined action of interferon and ribavirin against HCV infection is poorly understood. The exogenous administration of type 1 alpha interferon confers a nonspecific antiviral state which is characterized by the induction of a broad array of interferon-stimulated genes (ISGs). The principal actions of the ISGs are to block the initiation of viral protein synthesis and to decrease the stability of viral RNA, as well as to stimulate both the adaptive and the innate immune responses to infection (6). Clinically, interferon (most notably, its pegylated derivatives) has been demonstrated to induce multi-log-unit declines in the levels of plasma viremia. Ribavirin undergoes intracellular phosphorylation to its mono-, di-, and triphosphate derivatives. Ribavirin triphosphate is a low-affinity inhibitor of the viral NS5B polymerase and a substrate for incorporation into nascent genomic RNA. The utilization of ribavirin triphosphate as a substrate for RNA synthesis may ultimately inhibit viral RNA replication through error catastrophe. Ribavirin monophosphate competitively inhibits IMP dehydrogenase, which could deplete intracellular GTP levels, further augmenting the inhibitory effects of ribavirin triphosphate (6). Studies of ribavirin monotherapy indicate that it results in the transient and modest suppression of plasma viremia in some but not all patients (20); however, its greatest treatment benefit may be in suppressing the rebound of viremia following the completion of combination therapy with pegylated interferon. Treatment with pegylated alpha interferon and ribavirin is associated with a wide range of severe toxicities, including neuropsychiatric events, bone marrow toxicities, endocrine disorders, cardiovascular events, and anemia (25). In addition, ribavirin is teratogenic in multiple animal species. These observations underscore the need to discover and develop potent and specific antiviral agents that can augment the clinical anti-HCV activity of the current standard of care without increasing toxicity. Ultimately, it is envisioned that highly specific orally bioavailable antiviral agents could form the cornerstones of new treatment regimens that do not contain interferon and ribavirin.Several groups have confirmed that the replication of subgenomic and full-length HCV genomes depends on the expression of the host protein cyclophilin A (CyPA) (4, 14, 34). The levels of HCV RNA replication and viral protein production were reduced up to 1,000-fold in cell lines harboring the stable knockdown of CyPA expression. The knockdown of cyclophilin B, C, and D expression had no effect on HCV-specific RNA replication or protein production. The inhibition of replication was rescued by the overexpression of a wild-type CyPA escape mutant; however, the overexpression of a mutant CyPA containing the H126Q substitution (which abolishes peptidyl prolyl isomerase [PPIase] activity) did not rescue replication. These results further suggest that HCV RNA replication requires PPIase catalytic activity. The in vitro anti-HCV activity of cyclosporine (CsA) has been reported, thus confirming that the cyclophilins are potential drug targets (28). The potential clinical utility of cyclosporine-based inhibitors has been suggested by the introduction of nonimmunosuppressive analogs of CsA that retain cyclophilin binding activity. NIM 811 and Debio-025 contain modifications at the three sarcosine and the four methyl leucine residues. Both compounds inhibit HCV-specific RNA replication in vitro (17, 19). Clinical studies indicate that Debio-025 suppresses HCV plasma viremia when it is given as monotherapy for 14 days to patients coinfected with HIV-1 and HCV and when it is given as a component of a two-drug combination regimen with pegylated interferon for 28 days to HCV-monoinfected patients (8, 9).This report describes the preclinical profile of SCY-635, a 3,4-disubstituted nonimmunosuppressive CsA analog that exhibits potent suppression of HCV RNA replication in vitro. SCY-635 is a reversible, nanomolar inhibitor of the PPIase activity expressed by CyPA. SCY-635 is orally bioavailable in multiple species and distributes extensively to hepatocytes. Metabolic studies indicate that the administration of SCY-635 is unlikely to result in adverse pharmacological interactions. Two-drug synergy studies indicate that SCY-635 exhibits additive to synergistic antiviral activity when it is tested in vitro with alpha interferon 2b (IFNα-2b) or ribavirin without increasing cell cytotoxicity. These results are consistent with the recent observation of the potent clinical antiviral activity of SCY-635 (13) and suggest that further clinical studies assessing the safety and antiviral activity of SCY-635 in combination with interferon and ribavirin are warranted. 相似文献
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S. T. de Macedo-Silva G. Visbal J. A. Urbina W. de Souza J. C. F. Rodrigues 《Antimicrobial agents and chemotherapy》2015,59(10):6402-6418
Leishmaniases comprise a spectrum of diseases caused by protozoan parasites of the Leishmania genus. Treatments available have limited safety and efficacy, high costs, and difficult administration. Thus, there is an urgent need for safer and more-effective therapies. Most trypanosomatids have an essential requirement for ergosterol and other 24-alkyl sterols, which are absent in mammalian cells. In previous studies, we showed that Leishmania amazonensis is highly susceptible to aryl-quinuclidines, such as E5700, which inhibit squalene synthase, and to the azoles itraconazole (ITZ) and posaconazole (POSA), which inhibit C-14α-demethylase. Herein, we investigated the antiproliferative, ultrastructural, and biochemical effects of combinations of E5700 with ITZ and POSA against L. amazonensis. Potent synergistic antiproliferative effects were observed against promastigotes, with fractional inhibitory concentration (FIC) ratios of 0.0525 and 0.0162 for combinations of E5700 plus ITZ and of E5700 plus POSA, respectively. Against intracellular amastigotes, FIC values were 0.175 and 0.1125 for combinations of E5700 plus ITZ and E5700 plus POSA, respectively. Marked alterations of the ultrastructure of promastigotes treated with the combinations were observed, in particular mitochondrial swelling, which was consistent with a reduction of the mitochondrial transmembrane potential, and an increase in the production of reactive oxygen species. We also observed the presence of vacuoles similar to autophagosomes in close association with mitochondria and an increase in the number of lipid bodies. Both growth arrest and ultrastructural/biochemical alterations were strictly associated with the depletion of the 14-desmethyl endogenous sterol pool. These results suggest the possibility of a novel combination therapy for the treatment of leishmaniasis. 相似文献
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Pedro Miguel Salcedo Gómez Masayuki Amano Sofiya Yashchuk Akira Mizuno Debananda Das Arun K. Ghosh Hiroaki Mitsuya 《Antimicrobial agents and chemotherapy》2013,57(12):6110-6121
We designed, synthesized, and identified two novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitors (PIs), GRL-04810 and GRL-05010, containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, bis-tetrahydrofuranylurethane (bis-THF), and a difluoride moiety, both of which are active against the laboratory strain HIV-1LAI (50% effective concentrations [EC50s], 0.0008 and 0.003 μM, respectively) with minimal cytotoxicity (50% cytotoxic concentrations [CC50s], 17.5 and 37.0 μM, respectively, in CD4+ MT-2 cells). The two compounds were active against multi-PI-resistant clinical HIV-1 variants isolated from patients who had no response to various antiviral regimens. GRL-04810 and GRL-05010 also blocked the infectivity and replication of each of the HIV-1NL4-3 variants selected by up to 5 μM lopinavir (EC50s, 0.03 and 0.03 μM, respectively) and atazanavir (EC50s, 0.02 and 0.04 μM, respectively). Moreover, they were active against darunavir (DRV)-resistant variants (EC50 in 0.03 to 0.034 μM range for GRL-04810 and 0.026 to 0.043 μM for GRL-05010), while DRV had EC50s between 0.02 and 0.174 μM. GRL-04810 had a favorable lipophilicity profile as determined with the partition (log P) and distribution (log D) coefficients of −0.14 and −0.29, respectively. The in vitro blood-brain barrier (BBB) permeability assay revealed that GRL-04810 and GRL-05010 may have a greater advantage in terms of crossing the BBB than the currently available PIs, with apparent penetration indexes of 47.8 × 10−6 and 61.8 × 10−6 cm/s, respectively. The present data demonstrate that GRL-04810 and GRL-05010 exert efficient activity against a wide spectrum of HIV-1 variants in vitro and suggest that two fluorine atoms added to their bis-THF moieties may well enhance their penetration across the BBB. 相似文献
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Ajay Kumar Singh Krishna Misra 《Proceedings of the National Academy of Sciences, India. Section B.》2012,82(3):365-373
A 759 amino acid long sequence of polymerase PB2 [Influenza A virus {A/Mexico/47N/2009(H1N1)}] was taken to build the model of the protein which was validated by different tools of SAVS (structural analysis and verification server). The modeled protein was interacted with four different drugs available in the market viz. oseltaminivir, amantadine, zanasmivir, rimantadine (RS) and some naturally occurring compounds i.e. curcuminoids (curcumin, demethoxy curcumin, bis-demethoxy curcumin and cyclocurcumin) along with two synthetic bioconjugates of curcumin viz. dipiperoyl and disalicyloyl esters. The analysis parameters including docking score, reranking score and number of H-bonds indicate cyclocurcumin as the most favoured. 相似文献
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Yao Cheng Lun K. Tsou Jianfeng Cai Toshihiro Aya Ginger E. Dutschman Elizabeth A. Gullen Susan P. Grill Annie Pei-Chun Chen Brett D. Lindenbach Andrew D. Hamilton Yung-chi Cheng 《Antimicrobial agents and chemotherapy》2010,54(1):197-206
Recent years have seen the rapid advancement of new therapeutic agents against hepatitis C virus (HCV) in response to the need for treatment that is unmet by interferon (IFN)-based therapies. Most antiviral drugs discovered to date are small molecules that modulate viral enzyme activities. In the search for highly selective protein-binding molecules capable of disrupting the viral life cycle, we have identified a class of anionic tetraphenylporphyrins as potent and specific inhibitors of the HCV replicons. Based on the structure-activity relationship studies reported herein, meso-tetrakis-(3,5-dicarboxy-4,4′-biphenyl) porphyrin was found to be the most potent inhibitor of HCV genotype 1b (Con1) replicon systems but was less effective against the genotype 2a (JFH-1) replicon. This compound induced a reduction of viral RNA and protein levels when acting in the low nanomolar range. Moreover, the compound could suppress replicon rebound in drug-treated cells and exhibited additive to synergistic effects when combined with protease inhibitor BILN 2061 or with IFN-α-2a. Our results demonstrate the potential use of tetracarboxyphenylporphyrins as potent anti-HCV agents.Hepatitis C virus (HCV) exerts an increasingly heavy burden on global health care, and approximately 200 million people worldwide are infected (39). Chronically infected patients are often at risk for developing hepatic fibrosis, cirrhosis, and hepatocellular carcinoma (15). HCV is an enveloped virus that belongs to the Flaviviridae family, and seven recognized HCV genotypes and numerous subtypes have been identified. Genotype 1a is the most prevalent strain worldwide, and genotype 1b is predominant in Europe and North America, whereas genotype 2 is more prevalent in Asia (4, 33). The current standard of care, pegylated alpha interferon (IFN-α) combined with ribavirin, is plagued with adverse effects and has sustained viral response in less than half of the patients with genotype 1 infections (11, 20, 25). Therefore, more-effective and better-tolerated therapies are urgently needed, in particular for the treatment of nonresponders to IFN-based therapies.The HCV genome, which is a single-stranded positive-sense RNA about 9.6 kb in length, encodes a polyprotein that is cleaved by viral and host proteases into structural (core, E1, E2, and possibly p7) and nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) (4). The nonstructural proteins NS3 through NS5B assemble on the cytoplasmic membranes into a well-organized macromolecular machinery called the HCV replicase that is essential for the viral RNA replication (8, 14, 31). Until recently, the development of anti-HCV drugs had been hindered by the lack of a robust cell culture model. The establishment and optimization of the replicon systems have extensively widened our knowledge of the HCV replication and also proved a powerful tool for the discovery of novel agents that target the assembly and function of HCV replicase. HCV replicons are subgenomic constructs capable of autonomous replication in hepatoma cell lines, and the major viral components of the replicons consist of NS3 through NS5B (2, 23). Among these nonstructural proteins, viral protease NS3/4A and RNA-dependent RNA polymerase NS5B are the most extensively explored targets for anti-HCV drug development (for reviews, see references 6, 24, and 28). However, due to the error-prone nature of NS5B, mutational escapes could rapidly emerge under selective pressures from virus-specific inhibitors (35, 40). Other modalities under investigation include immune modulators and therapies targeting viral RNA.Protein-protein interactions often involve substantial interfacial areas larger than 1,000 Å2 (34). Yet, selective targeting of a surface region in order to alter a protein''s function or interaction with other biomolecules has not been extensively explored. In the current study, we have designed and synthesized a class of theoretical protein-binding molecules built on a porphyrin core, which is compatible with the biological milieu. The tetraphenylporphyrin (TPP) scaffold provides a sizable platform allowing hydrophobic interactions with the target surface, while charged peptidic appendages projected from the periphery support electrostatic interactions with complementary groups on the target(s). This contact with the large area may decrease the likelihood of high-level resistance developing in the targeted virus. We explored the potential of this class of compounds for antiviral activity against the HCV replicon systems. meso-Tetrakis-(3,5-dicarboxy-4,4′-biphenyl) porphyrin (compound 6) was found to be the most potent and selective inhibitor of HCV genotype 1b Con1 replicons (50% effective concentration [EC50], 0.024 ± 0.005 μM) with low cytotoxicity. While undertaking mechanistic studies to characterize the molecular target(s), we describe here the structure-activity relationships of tetraphenylporphyrin derivatives and the anti-HCV properties of compound 6, which is a proof-of-concept model for the development of proteomimetics in HCV drug discovery. 相似文献
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Deborah Butler Dongzhao Chen Karen O'Dwyer Thomas Lewandowski Kelly Aubart Magdalena Zalacain 《Antimicrobial agents and chemotherapy》2014,58(1):290-296
Peptide deformylase (PDF), a clinically unexploited antibacterial target, plays an essential role in protein maturation. PDF inhibitors, therefore, represent a new antibiotic class with a unique mode of action that provides an alternative therapy for the treatment of infections caused by drug-resistant pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). GSK1322322 is a novel PDF inhibitor that is in phase II clinical development for the treatment of lower respiratory tract and skin infections. We have discovered that PDF inhibitors can prevent S. aureus
in vitro growth for up to 6 h at concentrations 8- to 32-fold below their MICs. This phenomenon seems specific to PDF inhibitors, as none of the antimicrobial agents with alternative mechanisms of action tested show such a potent and widespread effect. It also appears limited to S. aureus, as PDF inhibitors do not show such an inhibition of growth at sub-MIC levels in Streptococcus pneumoniae or Haemophilus influenzae. Analysis of the effect of GSK1322322 on the early growth of 100 randomly selected S. aureus strains showed that concentrations equal to or below 1/8× MIC inhibited growth of 91% of the strains tested for 6 h, while the corresponding amount of moxifloxacin or linezolid only affected the growth of 1% and 6% of strains, respectively. Furthermore, the sub-MIC effect demonstrated by GSK1322322 appears more substantial on those strains at the higher end of the MIC spectrum. These effects may impact the clinical efficacy of GSK1322322 in serious infections caused by multidrug-resistant S. aureus. 相似文献