Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 4 de 4
Filter
Add more filters










Database
Publication year range
1.
Chem Pharm Bull (Tokyo) ; 56(10): 1400-5, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18827378

ABSTRACT

The severe acute respiratory syndrome (SARS) coronavirus 3CL protease is an attractive target for the development of anti-SARS drugs. In this paper, cinanserin (1) analogs were synthesized and tested for the inhibitory activities against SARS-coronavirus (CoV) 3CL protease by fluorescence resonance energy transfer (FRET) assay. Four analogs show significant activities, especially compound 26 with an IC(50) of 1.06 microM.


Subject(s)
Antiviral Agents/pharmacology , Cinanserin/analogs & derivatives , Cinanserin/pharmacology , Protease Inhibitors/pharmacology , Serotonin Antagonists/pharmacology , Severe acute respiratory syndrome-related coronavirus/enzymology , Viral Proteins/antagonists & inhibitors , Antiviral Agents/chemical synthesis , Cinanserin/chemical synthesis , Coronavirus 3C Proteases , Cysteine Endopeptidases , Drug Design , Fluorescence Resonance Energy Transfer , Indicators and Reagents , Magnetic Resonance Spectroscopy , Models, Molecular , Protease Inhibitors/chemical synthesis , Serotonin Antagonists/chemical synthesis , Spectrophotometry, Infrared , Structure-Activity Relationship
2.
Chem Pharm Bull (Tokyo) ; 56(8): 1147-52, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18670116

ABSTRACT

Novel potential human immunodeficiency virus (HIV) protease inhibitors were designed by a combination of nelfinavir and amprenavir motifs. The designed compounds were prepared by a facile synthetic route and their stereochemistry was further confirmed by a stereospecific synthesis from commercially available (S)-2-oxiranylmethyl m-nitrobenzenesulfonate. All compounds were tested for their ability in inhibiting HIV type 1 protease activity with the published method of reference 19. Derivatives 1a--u exhibited moderate to significant inhibitory activities in preliminary bioassay. The best compound 1a has IC50 value of 0.02 microM, comparable to that of amprenavir. A docking study on compounds 1a--u was performed using the published X-ray crystal structure of HIV type 1 protease, all compounds bound to the HIV type 1 protease in an extended conformation and the scaffoldings of the binding conformations could be aligned quite well. Comparative molecular field analysis (CoMFA) study was performed to explore the specific contributions of electrostatic and steric effects in the binding of these new compounds to HIV type 1 protease and a predictive CoMFA model was built with thirteen compounds as training set. Test analysis of other five compounds as test set demonstrated that the CoMFA model has strong predictive ability to this series of compounds. It will be very useful to further optimize the designed inhibitors.


Subject(s)
Anti-HIV Agents/chemical synthesis , HIV Protease Inhibitors/chemical synthesis , HIV/drug effects , Propanolamines/chemical synthesis , Anti-HIV Agents/pharmacology , Anti-HIV Agents/therapeutic use , Crystallography, X-Ray , Drug Design , HIV Infections/drug therapy , HIV Protease Inhibitors/pharmacology , HIV Protease Inhibitors/therapeutic use , Humans , Inhibitory Concentration 50 , Propanolamines/pharmacology , Propanolamines/therapeutic use , Structure-Activity Relationship
4.
J Virol ; 79(11): 7095-103, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15890949

ABSTRACT

The 3C-like proteinase (3CLpro) of severe acute respiratory syndrome-associated coronavirus (SARS-CoV) is one of the most promising targets for anti-SARS-CoV drugs due to its crucial role in the viral life cycle. In this study, a database containing structural information of more than 8,000 existing drugs was virtually screened by a docking approach to identify potential binding molecules of SARS-CoV 3CLpro. As a target for screening, both a homology model and the crystallographic structure of the binding pocket of the enzyme were used. Cinanserin (SQ 10,643), a well-characterized serotonin antagonist that has undergone preliminary clinical testing in humans in the 1960s, showed a high score in the screening and was chosen for further experimental evaluation. Binding of both cinanserin and its hydrochloride to bacterially expressed 3CLpro of SARS-CoV and the related human coronavirus 229E (HCoV-229E) was demonstrated by surface plasmon resonance technology. The catalytic activity of both enzymes was inhibited with 50% inhibitory concentration (IC50) values of 5 microM, as tested with a fluorogenic substrate. The antiviral activity of cinanserin was further evaluated in tissue culture assays, namely, a replicon system based on HCoV-229E and quantitative test assays with infectious SARS-CoV and HCoV-229E. All assays revealed a strong inhibition of coronavirus replication at nontoxic drug concentrations. The level of virus RNA and infectious particles was reduced by up to 4 log units, with IC50 values ranging from 19 to 34 microM. These findings demonstrate that the old drug cinanserin is an inhibitor of SARS-CoV replication, acting most likely via inhibition of the 3CL proteinase.


Subject(s)
Antiviral Agents/pharmacology , Cinanserin/pharmacology , Protease Inhibitors/pharmacology , Severe acute respiratory syndrome-related coronavirus/drug effects , Severe acute respiratory syndrome-related coronavirus/enzymology , Viral Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemistry , Base Sequence , Cell Line , Chlorocebus aethiops , Cinanserin/chemistry , Coronavirus 3C Proteases , Cricetinae , Cysteine Endopeptidases , DNA, Viral/genetics , Drug Evaluation, Preclinical/methods , Endopeptidases/chemistry , Endopeptidases/genetics , Humans , In Vitro Techniques , Models, Molecular , Protease Inhibitors/chemistry , RNA-Dependent RNA Polymerase/antagonists & inhibitors , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/genetics , Severe acute respiratory syndrome-related coronavirus/genetics , Severe acute respiratory syndrome-related coronavirus/physiology , User-Computer Interface , Vero Cells , Viral Proteins/chemistry , Viral Proteins/genetics , Virus Replication/drug effects
SELECTION OF CITATIONS
SEARCH DETAIL
...