Exploring the potent drugs for life-threatening viruses: Inhibition of 3C & 3C-Like Viral Proteases and Influenza Neuraminidase
Date Issued
2011
Date
2011
Author(s)
Tan, Kian-Pin
Abstract
Severe acute respiratory syndrome (SARS) is a highly contagious and fatal respiratory disease. It is caused by a novel coronavirus which never been discovered before the SARS, namely SARS-CoV. The outbreak of this deadly disease in 2003 had killed almost 10% of the infected patients. Although it has been 7 years since the last reported case of SARS, the evidences that bats are natural reservoirs of SARS-CoV have led to the concerns about the reemergence of the deadly disease. In search of the potential drugs against the deadly disease, SARS 3CLpro a protease which playing essential roles during the viral replication has been targeted for the drugs development. A series of pyrimidine compounds have been synthesized based on the findings that pyridine compounds could act as SARS 3CLpro reversible inhibitors. Furthermore, a series of pyrazolone compounds have also been synthesized as part of our laboratory’s continuation work of high throughput screenings. Some of the pyrazolone compounds have also been identified as common inhibitors for both 3C and 3CL protease, so that the Coxsackievirus B3 3Cpro have also been purified for further inhibition assay. The results show that one of the pyrimidine analogs could inhibit the SARS 3CLpro with an IC50 of 6.1μM. Meanwhile, a pyrazolone analog could inhibits SARS 3CLpro as well as inhibits CVB3 3Cpro with an IC50 of 8.4μM and 9.6μM respectively.
Influenza viruses are negative sense, single-stranded, segmented RNA viruses. It is the viruses which cause the seasonal flu and even flu pandemics. Two glycoproteins, hemagglutinin and neuraminidase play very crucial roles during the influenza virus infection and replication. Neuraminidase facilitates the release of the replicate viruses from the infected cells by enzymatically cleavage of the sialic acid groups from host glycoproteins and hence it is a very good target for drugs development. VK84, an original hit that inhibits the H5N1 neuraminidase with an IC50 of 16.6 μM has been modified based on the computer modeling and a series of analogs were then been synthesized. VK84 is also a pyrazolone compound and one of its analogs, VK94, inhibits the H1N1 neuraminidase with an IC50 of 1.7μM. According to the docking results, VK94 shows some unexpected H-bonds and this made VK94 as an attractive and potential inhibitor for further modifications as pyrazolone compounds that have never been reported as neuraminidase inhibitors.
Furthermore, in order to increase the accuracies and to save money and efforts for high throughput screening, Catalyst 4.10 was utilized to generate a reliable and predictive 3D-QSAR. The generated pharmacophore, Hypo1 has been validated and it seems that it is a reliable and predictive pharmacophore for virtual high throughput screening. In general, a complete procedure from the virtual high throughput screenings then to the inhibition assays has been developed.
Subjects
Severe acute respiratory syndrome
3C protease
3CL protease
Influenza virus
Neuraminidase
Pyrimidine
Pyrazolone
3D-QSAR pharmacophore
Type
thesis
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