Structure-based exploration and exploitation of the S4 subsite of norovirus 3CL protease in the design of potent and permeable inhibitors

Kankanamalage, Anushka C. Galasiti; Kim, Yun-Jeong; Rathnayake, Athri D.; Damalanka, Vishnu C.; Weerawarna, Pathum M.; Doyle, Seán; Alsoudi, Amer F; Dissanayake, D.M.P.; Lushington, Gerald H.; Mehzabeen, N.; Battaile, Kevin P.; Lovell, Scott; Chang, Kyung-Ro; Groutas, William C.

doi:10.1016/j.ejmech.2016.11.027

Cited by 21 publications

(23 citation statements)

References 45 publications

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“…Dipeptidyl aldehyde inhibitors lacking an oxazolidinone ring form an additional backbone H-bond with Gln110, which is not possible with the oxazolidinone inhibitors (since the oxazolidinone ring N lacks a hydrogen) [31]. Comparison of a previously determined inhibitor bound NV 3CLpro structure of the same crystal form (5T6D) [39] revealed a high degree of similarity with an RMSD deviation of 0.71 Å (154 residues) between Cα atoms using GESAMT (Figure 3B) [40]. However, significant differences are observed in β-strands bII and cII (Gly 92 to Leu 121) which contain Gln 110.…”

Section: Resultsmentioning

confidence: 99%

“…Intensities were integrated using XDS [41-k42] via Autoproc [43] and the Laue class analysis and data scaling were performed with Aimless [44]. Structure solution was conducted by molecular replacement with Phaser [45] using a previously determined isomorphous structure of inhibitor bound NV 3CLpro (PDB: 5T6D) [39] as the search model. Structure refinement and manual model building were conducted with Phenix [46] and Coot [47], respectively.…”

Section: Methodsmentioning

confidence: 99%

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Structure-guided design, synthesis and evaluation of oxazolidinone-based inhibitors of norovirus 3CL protease

Damalanka

Kim

Kankanamalage

et al. 2018

European Journal of Medicinal Chemistry

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Acute nonbacterial gastroenteritis caused by noroviruses constitutes a global public health concern and a significant economic burden. There are currently no small molecule therapeutics or vaccines for the treatment of norovirus infections. A structure-guided approach was utilized in the design of a series of inhibitors of norovirus 3CL protease that embody an oxazolidinone ring as a novel design element for attaining optimal binding interactions. Low micromolar cell-permeable inhibitors that display anti-norovirus activity have been identified. The mechanism of action, mode of binding, and structural rearrangements associated with the interaction of the inhibitors and the enzyme were elucidated using X-ray crystallography.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Structure-guided design, synthesis and evaluation of oxazolidinone-based inhibitors of norovirus 3CL protease

Damalanka

Kim

Kankanamalage

et al. 2018

European Journal of Medicinal Chemistry

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show abstract

“…Intensities were integrated using XDS via Autoproc and the Laue class analysis and data scaling were performed with Aimless . Structure solution was conducted by molecular replacement with Phaser using a previously determined isomorphous structure of inhibitor bound NV 3CLpro (PDB: 5T6D) as the search model. Structure refinement and manual model building were conducted with Phenix and Coot, respectively.…”

Section: Methodsmentioning

confidence: 99%

Putative structural rearrangements associated with the interaction of macrocyclic inhibitors with norovirus 3CL protease

et al. 2019

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Human noroviruses are the primary cause of outbreaks of acute gastroenteritis worldwide. The problem is further compounded by the current lack of norovirus‐specific antivirals or vaccines. Noroviruses have a single‐stranded, positive sense 7 to 8 kb RNA genome which encodes a polyprotein precursor that is processed by a virus‐encoded 3C‐like cysteine protease (NV 3CLpro) to generate at least six mature nonstructural proteins. Processing of the polyprotein is essential for virus replication, consequently, NV 3CLpro has emerged as an attractive target for the discovery of norovirus therapeutics and prophylactics. We have recently described the structure‐based design of macrocyclic transition state inhibitors of NV 3CLpro. In order to gain insight and understanding into the interaction of macrocyclic inhibitors with the enzyme, as well as probe the effect of ring size on pharmacological activity and cellular permeability, additional macrocyclic inhibitors were synthesized and high resolution cocrystal structures determined. The results of our studies tentatively suggest that the macrocyclic scaffold may hamper optimal binding to the active site by impeding concerted cross‐talk between the S2 and S4 subsites.

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“…Synthesis of NPI52 ( Prior et al, 2013 ), GC376 ( Kim et al, 2012 ), GC551 and GC543 ( Mandadapu et al, 2013a ), GC523 ( Mandadapu et al, 2012 ), GC583, GC587, GC591 and GC597 ( Galasiti Kankanamalage et al, 2015 ), GC772 and GC774 ( Galasiti Kankanamalage et al, 2017 ) were previously described. The compound list is shown in Table 1 .…”

Section: Methodsmentioning

confidence: 99%

Protease inhibitors broadly effective against feline, ferret and mink coronaviruses

et al. 2018

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Ferret and mink coronaviruses typically cause catarrhal diarrhea in ferrets and minks, respectively. In recent years, however, systemic fatal coronavirus infection has emerged in ferrets, which resembles feline infectious peritonitis (FIP) in cats. FIP is a highly fatal systemic disease caused by a virulent feline coronavirus infection in cats. Despite the importance of coronavirus infections in these animals, there are no effective commercial vaccines or antiviral drugs available for these infections. We have previously reported the efficacy of a protease inhibitor in cats with FIP, demonstrating that a virally encoded 3C-like protease (3CLpro) is a valid target for antiviral drug development for coronavirus infections. In this study, we extended our previous work on coronavirus inhibitors and investigated the structure-activity relationships of a focused library of protease inhibitors for ferret and mink 3CLpro. Using the fluorescence resonance energy transfer assay, we identified potent inhibitors broadly effective against feline, ferret and mink coronavirus 3CLpro. Multiple amino acid sequence analysis and modelling of 3CLpro of ferret and mink coronaviruses were conducted to probe the structural basis for these findings. The results of this study provide support for further research to develop broad-spectrum antiviral agents for multiple coronavirus infections. To the best of our knowledge, this is the first report on small molecule inhibitors of ferret and mink coronaviruses.

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Structure-based exploration and exploitation of the S4 subsite of norovirus 3CL protease in the design of potent and permeable inhibitors

Cited by 21 publications

References 45 publications

Structure-guided design, synthesis and evaluation of oxazolidinone-based inhibitors of norovirus 3CL protease

Structure-guided design, synthesis and evaluation of oxazolidinone-based inhibitors of norovirus 3CL protease

Putative structural rearrangements associated with the interaction of macrocyclic inhibitors with norovirus 3CL protease

Protease inhibitors broadly effective against feline, ferret and mink coronaviruses

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