Synthesis and Characterization of Bismuth-based Bicyclic Peptide Inhibitors Targeting Main Protease of SARS-CoV-2
Disciplines
Inorganic Chemistry | Medicinal-Pharmaceutical Chemistry | Organic Chemistry
Abstract (300 words maximum)
The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus and the resultant COVID-19 disease represent the most significant public health crisis of this century, exerting a profound impact on the global economy, as well as human health and lives. The main protease (Mpro) is a vital protease that facilitates viral replication. Inhibition of this viral protease enzyme blocks the formation of functional viral proteins required for the viral life cycle. Small molecules have been shown to improve antiviral activity, but with lots of side effects. Peptide therapeutics, in contrast, are highly attractive due to their selectivity, tolerability, and fewer adverse effects. However, they aren’t without limitations, which include poor metabolic stability, membrane permeability, and oral bioavailability. Bicycling has been found to improve these limitations. Solid-phase peptide synthesizer was used to synthesize the linear peptides 3CTLP1 and 3CTLP2. After the synthesis, the peptide-resin complex was cleaved with 82.5% trifluoroacetic acid. The cleaved peptides were filtered, precipitated, lyophilized, and characterized. The linear peptides show strong peaks at m/z 1658.58 and 830.42, 1865.00 and 933.42, respectively, corresponding to the +1 and +2 charge states. These linear peptides were further synthesized into Bismuth-based bicyclic analogs by adding tris(2-carboxyethyl) phosphine (TCEP)-NaOH and Bismuth (III)bromide. A pale-yellow coloration indicated the formation of a bicyclic product, which was centrifuged, reprecipitated, lyophilized, and characterized. The bicyclic peptides, Bi-3CTLP1, show strong peaks at 1865.71 and 932.86 (corresponding to +1 and +2 charge states), and Bi-3CTLP2 shows strong peaks at 1035.94 and 690.96 (corresponding to +2 and +3 charge states). Future work will be focused on their FRET, LC-MS SIM, and gastrointestinal assays of these analogs.
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Academic department under which the project should be listed
CSM – Chemistry and Biochemistry
Primary Investigator (PI) Name
Mohammad Halim
Synthesis and Characterization of Bismuth-based Bicyclic Peptide Inhibitors Targeting Main Protease of SARS-CoV-2
The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus and the resultant COVID-19 disease represent the most significant public health crisis of this century, exerting a profound impact on the global economy, as well as human health and lives. The main protease (Mpro) is a vital protease that facilitates viral replication. Inhibition of this viral protease enzyme blocks the formation of functional viral proteins required for the viral life cycle. Small molecules have been shown to improve antiviral activity, but with lots of side effects. Peptide therapeutics, in contrast, are highly attractive due to their selectivity, tolerability, and fewer adverse effects. However, they aren’t without limitations, which include poor metabolic stability, membrane permeability, and oral bioavailability. Bicycling has been found to improve these limitations. Solid-phase peptide synthesizer was used to synthesize the linear peptides 3CTLP1 and 3CTLP2. After the synthesis, the peptide-resin complex was cleaved with 82.5% trifluoroacetic acid. The cleaved peptides were filtered, precipitated, lyophilized, and characterized. The linear peptides show strong peaks at m/z 1658.58 and 830.42, 1865.00 and 933.42, respectively, corresponding to the +1 and +2 charge states. These linear peptides were further synthesized into Bismuth-based bicyclic analogs by adding tris(2-carboxyethyl) phosphine (TCEP)-NaOH and Bismuth (III)bromide. A pale-yellow coloration indicated the formation of a bicyclic product, which was centrifuged, reprecipitated, lyophilized, and characterized. The bicyclic peptides, Bi-3CTLP1, show strong peaks at 1865.71 and 932.86 (corresponding to +1 and +2 charge states), and Bi-3CTLP2 shows strong peaks at 1035.94 and 690.96 (corresponding to +2 and +3 charge states). Future work will be focused on their FRET, LC-MS SIM, and gastrointestinal assays of these analogs.