Chemokine Receptor CCR-5 Inhibitors Produced byChaetomiumglobosum

Yang, Shu‐Wei; Mierzwa, Ronald; Terracciano, Joseph; Patel, Mahesh; Gullo, Vincent P.; Wagner, Nicole; Baroudy, Bahige M.; Puar, Mohindar S.; Chan, Tze‐Ming; McPhail, and Andrew T.; Chu, Min

doi:10.1021/np060121y

Cited by 46 publications

(32 citation statements)

References 30 publications

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“…Comparative analysis of NMR and MASS revealed that compound ‘A’ is similar to Antibiotic Sch 210971 (m/z 445 and λ max 290) (Figure 8), which has previously been isolated from C. globosum by Yang et al (2006). In the finding by Yang et al molecular weight of the isolated compound was 445 Da and showed the protonated molecular ion at m/z + 446 similar to the compound isolated by us.…”

Section: Resultsmentioning

confidence: 68%

“…methanol and ethyl acetate were more active than hexane extract against S. sclerotiorum . Antibiotic Sch 210971 has been previously reported as chemokine receptor CCR-5 inhibitor (Yang et al 2006); however this is the first report of antifungal activity of this compound. HPLC has been utilized for the first time in our study in finding out the principle component of C. globosum responsible for antifungal activity.…”

Section: Discussionmentioning

confidence: 86%

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Identification of antifungal principle in the solvent extract of an endophytic fungus Chaetomium globosum from Withania somnifera

2013

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Extracts of Chaetomium globosum EF18, isolated as endophytic fungus from Withania somnifera, were found effective against Sclerotinia sclerotiorum. Ethyl acetate and methanol extracts were more effective than hexane extract showing >80% growth inhibition. Bioactive compound (antibiotic Sch 210971, m/z 445 and λmax 290) having antifungal activity against S. sclerotiorum has been isolated in pure form from the ethyl acetate extract following bioassay guided fractionation. Apart from this compound other fractions of polar to medium polarity were also found effective. Fraction no. VIII from VLC (Vacuum liquid chromatography) column of ethyl acetate extract was most active having IC50 value 35.4 μg/ml.

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Section: Resultsmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 86%

Identification of antifungal principle in the solvent extract of an endophytic fungus Chaetomium globosum from Withania somnifera

2013

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“…This compound exhibits unique inhibitory activity against CCR-5, a cell surface receptor that allows the entry of HIV-1 into cells, and is an attractive lead compound for novel anti-HIV therapeutics. [8] Previous studies have shown that the tetramic acid moieties in related compounds, such as equisetin 2 [9] (Scheme 1) and cyclopiazonic acid [10] , are formed via a Dieckmann-type condensation that is catalyzed by reductive domains located at the C-termini of polyketide synthase nonribosomal peptide synthetase hybrid megaenzymes (PKS–NRPSs) [11] . Thus, we hypothesized that the framework of 1 was also biosynthesized by a hybrid PKS–NRPS.…”

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confidence: 99%

Involvement of Lipocalin‐like CghA in Decalin‐Forming Stereoselective Intramolecular [4+2] Cycloaddition

et al. 2015

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Understanding enzymatic Diels—Alder (DA) reactions that can form complex natural product scaffold is of considerable interest. Sch 210972 1, a potential anti-HIV fungal natural product, contains a decalin core that is proposed to form via a DA reaction. We identified the gene cluster responsible for the biosynthesis of 1 and heterologously reconstituted the biosynthetic pathway in Aspergillus nidulans to characterize the enzymes involved. Most notably, deletion of cghA resulted in a loss of stereoselective decalin core formation, yielding both an endo 1 and a diastereomeric exo adducts of the proposed DA reaction. Complementation with cghA restored the sole formation of 1. Density functional theory computation of the proposed DA reaction provided a plausible explanation of the observed pattern of product formation. Based on our study, we propose that lipocalin-like CghA is responsible for the stereoselective intramolecular [4+2] cycloaddition that forms the decalin core of 1.

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“…Yang and coworkers in 2006 screened secondary metabolites from the microbial extracts of fungi, actinomycetes, or bacteria [106]. A high-throughput screening utilizing a radioactive CCR5-binding assay that inhibited RANTES binding was conducted on the extracts and led to the discovery of two tetramic acids Sch210971 ( 45 , Figure 6) and Sch210972 ( 46 , Figure 6) with an IC 50 of 1.2 μM and 79 nM, respectively.…”

Section: Second-generation Small-molecule Ccr5 Antagonistsmentioning

confidence: 99%

CCR5 receptor antagonists in preclinical to phase II clinical development for treatment of HIV

Kim

Giesler

Tahirovic

et al. 2016

Expert Opinion on Investigational Drugs

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Introduction The chemokine receptor CCR5 has garnered significant attention in recent years as a target to treat HIV infection largely due to the approval and success of the drug Maraviroc. The side effects and inefficiencies with other first generation agents led to failed clinical trials, prompting the development of newer CCR5 antagonists. Areas covered This review aims to survey the current status of ‘next generation’ CCR5 antagonists in the preclinical pipeline with an emphasis on emerging agents for the treatment of HIV infection. These efforts have culminated in the identification of advanced second-generation agents to reach the clinic and the dual CCR5/CCR2 antagonist Cenicriviroc as the most advanced currently in phase II clinical studies. Expert opinion The clinical success of CCR5 inhibitors for treatment of HIV infection has rested largely on studies of Maraviroc and a second-generation dual CCR5/CCR2 antagonist Cenicriviroc. Although research efforts identified several promising preclinical candidates, these were dropped during early clinical studies. Despite patient access to Maraviroc, there is insufficient enthusiasm surrounding its use as front-line therapy for treatment of HIV. The non-HIV infection related development activities for Maraviroc and Cenicriviroc may help drive future interests.

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Chemokine Receptor CCR-5 Inhibitors Produced byChaetomiumglobosum

Cited by 46 publications

References 30 publications

Identification of antifungal principle in the solvent extract of an endophytic fungus Chaetomium globosum from Withania somnifera

Identification of antifungal principle in the solvent extract of an endophytic fungus Chaetomium globosum from Withania somnifera

Involvement of Lipocalin‐like CghA in Decalin‐Forming Stereoselective Intramolecular [4+2] Cycloaddition

CCR5 receptor antagonists in preclinical to phase II clinical development for treatment of HIV

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