Imidazo[1,2-<i>a</i>]pyridines That Directly Interact with Hepatitis C NS4B: Initial Preclinical Characterization

Shotwell, J. Brad; Baskaran, Sundarababu; Chong, Pek Y.; Creech, Katrina L.; Crosby, Renae M.; Dickson, Hamilton D.; Fang, Jing; Garrido, Dulce; Mathis, Amanda; Maung, Jack; Parks, Derek J.; Pouliot, Jeffrey J.; Price, Daniel J.; Rai, Roopa; Seal, John W.; Schmitz, Uli; Tai, Vincent W.‐F.; Thomson, Michael M.; Xie, Meng; Xiong, Zhiping; Peat, Andrew J.

doi:10.1021/ml300090x

Cited by 47 publications

(54 citation statements)

References 9 publications

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“…NS5A-Syn activity in combination with DCV on WT gt 1a and 1b replicons is masked by the picomolar potency of DCV; however, the effects of the combination on DCV-resistant variants (gt 1a Q30E and gt 1b L31VϩY93H) are dramatic (30). The EC 50 on gt 1a Q30E of Syn-690 in combination with DCV at a concentration that approximates the EC 50 (200 nM) is enhanced Ͼ9,000-fold compared to that for Syn-690 alone (EC 50 , 0.006 versus 57 nM, respectively), and the EC 50 for Syn-535 in combination with DCV (200 nM) is enhanced Ͼ40,000-fold compared to that with Syn-535 alone (0.67 pM versus 28 nM, respectively). These comparisons demonstrate the ability of Syn-690 and Syn-535 to enhance the inhibitory potential of DCV on DCVresistant variants (Table 2).…”

Section: Resultsmentioning

confidence: 99%

“…The EC 50 profiles of DCV, Syn-690, and Syn-535 differ dramatically in gts 1a and 1b WT versus clinically significant DCV-resistant variants (Table 2) (3). NS5A-Syn activity in combination with DCV on WT gt 1a and 1b replicons is masked by the picomolar potency of DCV; however, the effects of the combination on DCV-resistant variants (gt 1a Q30E and gt 1b L31VϩY93H) are dramatic (30).…”

Section: Resultsmentioning

confidence: 99%

“…Asparagine (N) and arginine (R) substitutions at Y93 (ϳ50% each) cause an ϳ40,000 -fold increase in EC 50 versus that of DCV (31). The treatment of DCV-resistant virus with DCV-Syn-690 selected an additional change at serine (S) 38 (Table 3).…”

Section: Resultsmentioning

confidence: 99%

“…The sequence of the rebound virus from DCV treatment showed the emergence of F28S (Table 3). The F28S substitution in the 2a L31M background has been shown to arise with DCV selection and confer a high level of resistance to DCV (EC 50 , Ͼ1.8 M) (3). The sequence of the rebound virus from Syn-535 treatment showed the emergence of threonine at S38 (S38T).…”

Section: Resultsmentioning

confidence: 99%

“…Novel mutations observed following exposure to DCV-NS5A-Syn are less well characterized due to technical challenges caused by their low replication capacity (data not shown). Preliminary investigations using transient assays suggest that the S38F substitution does not significantly change the sensitivity of NS5A to DCV, with an estimated EC 50 of ϳ61 pM on the gt 1a replicon with the S38F substitution. However, the linked substitutions S38F and Y93H yielded an EC 50 estimate of Ͼ2 M for DCV (C. Wang, unpublished data).…”

Section: Discussionmentioning

confidence: 99%

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Synergistic Activity of Combined NS5A Inhibitors

O’Boyle

Nower

Gao

et al. 2016

Antimicrob Agents Chemother

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). To extend the characterization of NS5 A synergists, we tested new combinations of DCV and NS5A synergists against genotype (gt) 1 to 6 replicons and gt 1a, 2a, and 3a viruses. The kinetics of inhibition in HCV-infected cells treated with DCV, an NS5A synergist (NS5A-Syn), or a combination of DCV and NS5A-Syn were distinctive. Similar to activity observed clinically, DCV caused a multilog drop in HCV, followed by rebound due to the emergence of resistance. DCV-NS5A-Syn combinations were highly efficient at clearing cells of viruses, in line with the trend seen in replicon studies. The retreatment of resistant viruses that emerged using DCV monotherapy with DCV-NS5A-Syn resulted in a multilog drop and rebound in HCV similar to the initial decline and rebound observed with DCV alone on wild-type (WT) virus. A triple combination of DCV, NS5A-Syn, and a DAA targeting the NS3 or NS5B protein cleared the cells of viruses that are highly resistant to DCV. Our data support the observation that the cooperative interaction of DCV and NS5A-Syn potentiates both the genotype coverage and resistance barrier of DCV, offering an additional DAA option for combination therapy and tools for explorations of NS5A function. Hepatitis C virus (HCV) infections can be effectively cured using combinations of small-molecule direct-acting antivirals (DAAs) with different mechanisms of action. The nonstructural 5A replication complex inhibitor (NS5A RCI) class of compounds represented by daclatasvir (DCV) (BMS-790052, Daklinza; Bristol-Myers Squibb) has activity against genotypes (gts) 1a, 1b, 2a, 3a, 4a, 5a, and 6a and is the most potent class of HCV inhibitor yet described (1-3). NS3 protease inhibitors and NS5B polymerase inhibitors have thus far been the preferred DAA partners for DCV combination therapies (1). Combinations of small-molecule DAAs are required for effective curative oral therapies, because resistant variants existing in the quasispecies population in untreated HCV-infected patients are enriched during monotherapy. To prevent viral breakthrough or relapse and selection of resistant variants, multiple highly effective pangenotypic DAA combination therapies, with NS5A RCIs as the backbone, have been approved or are currently being developed (1, 4, 5).The binding site(s) for NS5A RCIs has been modeled based on biochemical and crystal structure data, implicating at least one site that spans a region between NS5A proteins that associate as dimers (6). Available evidence for NS5A inhibitor binding suggests that NS5A RCIs, such as DCV, bind tightly and specifically to NS5A protein dimers present in infected cells (6).A recent report (7) of DCV binding to Escherichia coli-expressed NS5A protein provided the first direct evidence that DCV binds to NS5A. The authors demonstrated that DCV binding can reduce the affinity of NS5A protein for viral RNA, supporting one potential mechanism of inhibition. An additional report of direct binding to NS5A protein of DCV and the related compound ledipasvir also supports the direct associatio...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Synergistic Activity of Combined NS5A Inhibitors

O’Boyle

Nower

Gao

et al. 2016

Antimicrob Agents Chemother

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Bicyclic Pyridines Containing Ring‐Junction Nitrogen

2018

Privileged Structures in Drug Discovery

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Recent Advances in Radical C−H Bond Functionalization of Imidazoheterocycles

et al. 2020

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Direct CÀ H bond functionalization through radical pathway has emerged as a powerful and ideal strategy for the synthesis of organic compounds. This review provides an overview of recent developments in radical CÀ H functionalization of imidazoheterocycles such as imidazo[1,2-a] pyridine, benzo[d]imidazo[2,1-b]thiazole, imidazo [2,1-b]thiazole, imidazo[1,2-a]pyrimidine, imidazo [2,1-a]isoquinoline, imidazo[1,2-a]pyrazine and imidazo[1,2-a]quinoline using organic peroxides, photo/electric-induced protocols, iodine-based reagents, first-row transition metal catalysts (Fe, Mn, Ni and Cu) and inorganic oxidants/or

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Imidazo[1,2-a]pyridines That Directly Interact with Hepatitis C NS4B: Initial Preclinical Characterization

Cited by 47 publications

References 9 publications

Synergistic Activity of Combined NS5A Inhibitors

Synergistic Activity of Combined NS5A Inhibitors

Bicyclic Pyridines Containing Ring‐Junction Nitrogen

Recent Advances in Radical C−H Bond Functionalization of Imidazoheterocycles

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