Bioorg Med Chem. 2015 Sep 1;23(17):6036-48. doi: 10.1016/j.bmc.2015.06.039. Epub 2015 Jun 19.
Targeting zoonotic viruses: Structure-based inhibition of the 3C-like protease from bat coronavirus HKU4--The likely reservoir host to the human coronavirus that causes Middle East Respiratory Syndrome (MERS).
The
bat coronavirus HKU4 belongs to the same 2c lineage as that of the
deadly Middle East Respiratory Syndrome coronavirus (MERS-CoV) and shows
high sequence similarity, therefore potentiating a threat to the human
population through a zoonotic shift or 'spill over' event. To date,
there are no effective vaccines or antiviral treatments available that
are capable of limiting the pathogenesis of any human coronaviral
infection. An attractive target for the development of anti-coronaviral
therapeutics is the 3C-like protease (3CL(pro)), which is essential for
the progression of the coronaviral life cycle. Herein, we report the
screening results of a small, 230-member peptidomimetic library against
HKU4-CoV 3CL(pro) and the identification of 43 peptidomimetic compounds
showing good to excellent inhibitory potency of HKU4-CoV 3CL(pro) with
IC50 values ranging from low micromolar to sub-micromolar. We
established structure-activity relationships (SARs) describing the
important ligand-based features required for potent HKU4-CoV 3CL(pro)
inhibition and identified a seemingly favored peptidic backbone for
HKU4-CoV 3CL(pro) inhibition. To investigate this, a molecular
sub-structural analysis of the most potent HKU4-CoV 3CL(pro) inhibitor
was accomplished by the synthesis and testing of the lead peptidomimetic
inhibitor's sub-structural components, confirming the activity of the
favored backbone (22A) identified via SAR analysis. In order to
elucidate the structural reasons for such potent HKU4-CoV 3CL(pro)
inhibition by the peptidomimetics having the 22A backbone, we determined
the X-ray structures of HKU4-CoV 3CL(pro) in complex with three
peptidomimetic inhibitors. Sequence alignment of HKU4-CoV 3CL(pro), and
two other lineage C Betacoronaviruses 3CL(pro)'s, HKU5-CoV and MERS-CoV
3CL(pro), show that the active site residues of HKU4-CoV 3CL(pro) that
participate in inhibitor binding are conserved in HKU5-CoV and MERS-CoV
3CL(pro). Furthermore, we assayed our most potent HKU4-CoV 3CL(pro)
inhibitor for inhibition of HKU5-CoV 3CL(pro) and found it to have
sub-micromolar inhibitory activity (IC50=0.54±0.03μM). The X-ray
structures and SAR analysis reveal critical insights into the structure
and inhibition of HKU4-CoV 3CL(pro), providing fundamental knowledge
that may be exploited in the development of anti-coronaviral
therapeutics for coronaviruses emerging from zoonotic reservoirs.
Copyright © 2015 Elsevier Ltd. All rights reserved.
KEYWORDS:
3C-like protease; Broad-spectrum inhibitors; Coronavirus; HKU4; HKU5; MERS; Peptidomimetic compounds; Protease inhibitors; SARS; Zoonotic reservoir- PMID:
- 26190463
- PMCID:
- PMC5433438
- DOI:
- 10.1016/j.bmc.2015.06.039
- [Indexed for MEDLINE]
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