Citrinin hydrate and radicinin: Human rhinovirus 3C-protease inhibitors discovered in a target-directed microbial screen.

Kadam, Sunil; Poddig, Jennifer B.; Humphrey, Pat; Karwowski, James P.; Jackson, Marianna; Tennent, Shaun; Fung, Lucy; Hochlowski, Jill E.; Rasmussen, Ronald R.; McAlpine, James B.

doi:10.7164/antibiotics.47.836

Cited by 28 publications

(31 citation statements)

References 11 publications

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“…Therefore, the coronaviral 3CLP is likely to be a key factor in the maturation of ORF1 products and hence in viral replication. The development of specific 3C proteinase inhibitors for use in the control of picornavirus infections has been considered (20,31) and is attractive, given the unique mode of action of the 3C proteinases. Such countermeasures could eventually be adopted for use against coronaviruses.…”

Section: Discussionmentioning

confidence: 99%

Characterization in vitro of an autocatalytic processing activity associated with the predicted 3C-like proteinase domain of the coronavirus avian infectious bronchitis virus

Tibbles

Brierley

Cavanagh

et al. 1996

J Virol

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A region of the infectious bronchitis virus (IBV) genome between nucleotide positions 8693 and 10927 which encodes the predicted 3C-like proteinase (3CLP) domain and several potential cleavage sites has been cloned into a T7 transcription vector. In vitro translation of synthetic transcripts generated from this plasmid was not accompanied by detectable processing activity of the nascent polypeptide unless the translation was carried out in the presence of microsomal membrane preparations. The processed products so obtained closely resembled in size those expected from cleavage at predicted glutamine-serine (Q/S) dipeptides and included a protein with a size of 35 kDa (p35) that corresponds to the predicted size of 3CLP. Efficient processing was dependent on the presence of membranes during translation; processing was found to occur when microsomes were added posttranslationally, but only after extended periods of incubation. C-terminal deletion analysis of the encoded polyprotein fragment revealed that cleavage activity was dependent on the presence of most but not all of the downstream and adjacent hydrophobic region MP2. Dysfunctional mutagenesis of the putative active-site cysteine residue of 3CLP to either serine or alanine resulted in polypeptides that were impaired for processing, while mutagenesis at the predicted Q/S release sites implicated them in the release of the p35 protein. Processed products of the wild-type protein were active in trans cleavage assays, which were used to demonstrate that the IBV 3CLP is sensitive to inhibition by both serine and cysteine protease class-specific inhibitors. These data reveal the identity of the IBV 3C-like proteinase, which exhibits characteristics in common with the 3C proteinases of picornaviruses.

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Section: Discussionmentioning

confidence: 99%

Characterization in vitro of an autocatalytic processing activity associated with the predicted 3C-like proteinase domain of the coronavirus avian infectious bronchitis virus

Tibbles

Brierley

Cavanagh

et al. 1996

J Virol

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“…[365][366][367] These include naphtoquinonelactol (compound XXX, Table II), 367 a quinine-like citrinin (compound XXXI, Table II), 366 radicinin (compound XXXII, Table II) 366 and triterpene sulfates (compound XXXIII, Table II). 365 These compounds show moderate IC 50 values in the mg/mL or millimolar range.…”

Section: Microbial Extractsmentioning

confidence: 99%

Selective inhibitors of picornavirus replication

Palma

Vliegen

Clercq

et al. 2008

Medicinal Research Reviews

225

215

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Picornaviruses cover a large family of pathogens that have a major impact on human but also on veterinary health. Although most infections in man subside mildly or asymptomatically, picornaviruses can also be responsible for severe, potentially life-threatening disease. To date, no therapy has been approved for the treatment of picornavirus infections. However, efforts to develop an antiviral that is effective in treating picornavirus-associated diseases are ongoing. In 2007, Schering-Plough, under license of ViroPharma, completed a phase II clinical trial with Pleconaril, a drug that was originally rejected by the FDA after a New Drug Application in 2001. Rupintrivir, a rhinovirus protease inhibitor developed at Pfizer, reached clinical trials but was recently halted from further development. Finally, Biota's HRV drug BTA-798 is scheduled for phase II trials in 2008. Several key steps in the picornaviral replication cycle, involving structural as well as non-structural proteins, have been identified as valuable targets for inhibition. The current review aims to highlight the most important developments during the past decades in the search for antivirals against picornaviruses.

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“…This enzyme, necessary for post-translation seission of the main viral polyprotein, is also suppressed by the antibiotic radieidin (XXIX) that is structurally similar to eitrinin and produced by Curvalaria sp. [115].…”

Section: Antibiotics Inhibiting the Late Stages Of Cholesterol Biosynmentioning

confidence: 95%

Antibiotics inhibiting the biosynthesis of cholesterol (a review)

Тренин

Катруха

1997

Pharm Chem J

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The several decades that have passed since the introduction of penicillin into medical practice is essentially the age of antibiotics. Their wide application was very fruitful and allowed the solution of a number of fundamental problems both in the field of infection pathology and in treating diseases of a non-infection nature [ 1,2]. As is well known, antibiotics are not only successfully used as antimicrobial preparations, but are also applied in oncology as antitumor drugs. Moreover, it was the discovery of microbial metabolites-immunomodulators and the creation of immunodepressants such as eyclosporin A and FK 506 that made possible surgical operations involving the transplantation of organs and tissues [3 -5].

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Citrinin hydrate and radicinin: Human rhinovirus 3C-protease inhibitors discovered in a target-directed microbial screen.

Abstract: HumanRhinoviruses belong to one of the largest family of positive sense RNAviruses; the Picornaviridae, which includes humanpathogens such as enteroviruses (poliovirus, coxsackeivirus, echovirus

Cited by 28 publications

References 11 publications

Characterization in vitro of an autocatalytic processing activity associated with the predicted 3C-like proteinase domain of the coronavirus avian infectious bronchitis virus

Characterization in vitro of an autocatalytic processing activity associated with the predicted 3C-like proteinase domain of the coronavirus avian infectious bronchitis virus

Selective inhibitors of picornavirus replication

Antibiotics inhibiting the biosynthesis of cholesterol (a review)

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