Sch 213766, A Novel Chemokine Receptor CCR-5 Inhibitor from Chaetomium globosum

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

doi:10.1038/ja.2007.67

Cited by 29 publications

(22 citation statements)

References 31 publications

(13 reference statements)

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“…In an effort to search for CCR-5 antagonists as potential leads for development, three novel CCR-5 inhibitors, Sch 210971 (59), Sch 210972 (60), and Sch 213766 (61), were reported from C. globosum Mer-0229, isolated from leaves of evergreen plants in Tucson, Arizona [68,69]. The relative configuration of 60 was determined by X-ray crystallographic analysis.…”

Section: Tetramic Acidsmentioning

confidence: 99%

Chemical and Bioactive Diversities of the Genus Chaetomium Secondary Metabolites

Zhang

Li²,

Zong³

et al. 2012

MRMC

117

102

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The genus Chaetomium fungi are considered to be a rich source of novel and bioactive secondary metabolites of great importance. Up till now, a variety of more than 200 secondary metabolites belonging to diverse structural types of chaetoglobosins, epipolythiodioxopiperazines, azaphilones, xanthones, anthraquinones, chromones, depsidones, terpenoids, and steroids have been discovered. Most of these fungal metabolites exhibited antitumor, cytotoxic, antimalarial, enzyme inhibitory, antibiotic, and other activities. This review covers the extraction, structure elucidation, structural diversity, and biological activities of natural products isolated from about 30 fungi associated with marine- and terrestrial- origins, and highlights some bioactive compounds as well as their mechanisms of action and structure-activity relationships.

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Section: Tetramic Acidsmentioning

confidence: 99%

Chemical and Bioactive Diversities of the Genus Chaetomium Secondary Metabolites

Zhang

Li²,

Zong³

et al. 2012

MRMC

117

102

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“…Many members of Chaetomiaceae have their natural habitat in soil or on mammal dung. A possible explanation of their recurrent virulence may lie in physiological properties such as growth at the human body temperature of 37°C, and the production of secondary metabolites such as inhibitors of chemokines and TNF-α [25], [26]. Particularly the fatal brain infections, which were repeatedly reported in Achaetomium strumarium (synonym of Chaetomium strumarium ) [27], [28], in C. atrobrunneum [19], and in Thielavia subthermophila [21], all belonging to the Chaetomiaceae , are remarkable.…”

Section: Discussionmentioning

confidence: 99%

Phylogenetic Findings Suggest Possible New Habitat and Routes of Infection of Human Eumyctoma

et al. 2013

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Eumycetoma is a traumatic fungal infection in tropical and subtropical areas that may lead to severe disability. Madurella mycetomatis is one of the prevalent etiologic agents in arid Northeastern Africa. The source of infection has not been clarified. Subcutaneous inoculation from plant thorns has been hypothesized, but attempts to detect the fungus in relevant material have remained unsuccessful. The present study aims to find clues to reveal the natural habitat of Madurella species using a phylogenetic approach, i.e. by comparison of neighboring taxa with known ecology. Four species of Madurella were included in a large data set of species of Chaetomium, Chaetomidium, Thielavia, and Papulaspora (n = 128) using sequences of the universal fungal barcode gene rDNA ITS and the partial LSU gene sequence. Our study demonstrates that Madurella species are nested within the Chaetomiaceae, a family of fungi that mainly inhabit animal dung, enriched soil, and indoor environments. We hypothesize that cattle dung, ubiquitously present in rural East Africa, plays a significant role in the ecology of Madurella. If cow dung is an essential factor in inoculation by Madurella, preventative measures may involve the use of appropriate footwear in addition to restructuring of villages to reduce the frequency of contact with etiologic agents of mycetoma. On the other hand, the Chaetomiaceae possess a hidden clinical potential which needs to be explored.

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“…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. The following year, the same group identified a third metabolite Sch213766 ( 47 , Figure 6) that had an IC 50 of 8.6 μM [107]. Tetramic acid compounds are known antimicrobials, but it is the first time that it has been described to have CCR5 activity.…”

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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Sch 213766, A Novel Chemokine Receptor CCR-5 Inhibitor from Chaetomium globosum

Cited by 29 publications

References 31 publications

Chemical and Bioactive Diversities of the Genus Chaetomium Secondary Metabolites

Chemical and Bioactive Diversities of the Genus Chaetomium Secondary Metabolites

Phylogenetic Findings Suggest Possible New Habitat and Routes of Infection of Human Eumyctoma

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

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