Dataset Information

Alkylidene Oxapenem ?-Lactamase Inhibitors Revisited: Potent Broad Spectrum Activity but New Stability Challenges.

ABSTRACT: We present a comprehensive study of C6-alkylidene containing oxapenems. We show that this class of ?-lactamase inhibitors possesses an unprecedented spectrum with activity against class A, C, and D enzymes. Surprisingly, this class of compounds displayed significant photolytic instability in addition to the known hydrolytic instability. Quantum mechanical calculations were used to develop models to predict the stability of new analogues.

SUBMITTER: Miller MD

PROVIDER: S-EPMC4137382 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Publications

Alkylidene Oxapenem β-Lactamase Inhibitors Revisited: Potent Broad Spectrum Activity but New Stability Challenges.

Miller Matthew D MD Kale Manoj M Reddy Kishore K Tentarelli Sharon S Zambrowski Mark M Zhang Minli M Palmer Tiffany T Breen John J Lahiri Sushmita S Shirude Pravin S PS Verheijen Jeroen C JC

ACS medicinal chemistry letters 20140620 8

We present a comprehensive study of C6-alkylidene containing oxapenems. We show that this class of β-lactamase inhibitors possesses an unprecedented spectrum with activity against class A, C, and D enzymes. Surprisingly, this class of compounds displayed significant photolytic instability in addition to the known hydrolytic instability. Quantum mechanical calculations were used to develop models to predict the stability of new analogues. ...[more]

PMID: 25147614

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Project description:Coronaviruses (CoVs) act as cross-species viruses and have the potential to spread rapidly into new host species and cause epidemic diseases. Despite the severe public health threat of severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome CoV (MERS-CoV), there are currently no drugs available for their treatment; therefore, broad-spectrum inhibitors of emerging and endemic CoVs are urgently needed. To search for effective inhibitory agents, we performed high-throughput screening (HTS) of a 2,000-compound library of approved drugs and pharmacologically active compounds using the established genetically engineered human CoV OC43 (HCoV-OC43) strain expressing Renilla luciferase (rOC43-ns2Del-Rluc) and validated the inhibitors using multiple genetically distinct CoVs in vitro We screened 56 hits from the HTS data and validated 36 compounds in vitro using wild-type HCoV-OC43. Furthermore, we identified seven compounds (lycorine, emetine, monensin sodium, mycophenolate mofetil, mycophenolic acid, phenazopyridine, and pyrvinium pamoate) as broad-spectrum inhibitors according to their strong inhibition of replication by four CoVs in vitro at low-micromolar concentrations. Additionally, we found that emetine blocked MERS-CoV entry according to pseudovirus entry assays and that lycorine protected BALB/c mice against HCoV-OC43-induced lethality by decreasing viral load in the central nervous system. This represents the first demonstration of in vivo real-time bioluminescence imaging to monitor the effect of lycorine on the spread and distribution of HCoV-OC43 in a mouse model. These results offer critical information supporting the development of an effective therapeutic strategy against CoV infection.IMPORTANCE Currently, there is no approved therapy to treat coronavirus infection; therefore, broad-spectrum inhibitors of emerging and endemic CoVs are needed. Based on our high-throughput screening assay using a compound library, we identified seven compounds with broad-spectrum efficacy against the replication of four CoVs in vitro Additionally, one compound (lycorine) was found to protect BALB/c mice against HCoV-OC43-induced lethality by decreasing viral load in the central nervous system. This inhibitor might offer promising therapeutic possibilities for combatting novel CoV infections in the future.

Dataset Information

Alkylidene Oxapenem ?-Lactamase Inhibitors Revisited: Potent Broad Spectrum Activity but New Stability Challenges.

Publications

Alkylidene Oxapenem β-Lactamase Inhibitors Revisited: Potent Broad Spectrum Activity but New Stability Challenges.

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