key: cord-338296-2hk7h132
authors: Malla, Tek Narsingh; Pandey, Suraj; Poudyal, Ishwor; Feliz, Denisse; Noda, Moraima; Phillips, George; Stojkovic, Emina; Schmidt, Marius
title: Ebselen Reacts with SARS Coronavirus-2 Main Protease Crystals
date: 2020-08-23
journal: bioRxiv
DOI: 10.1101/2020.08.10.244525
sha: 
doc_id: 338296
cord_uid: 2hk7h132

The SARS coronavirus 2 main protease 3CLpro tailor cuts various essential virus proteins out of long poly-protein translated from the virus RNA. If the 3CLpro is inhibited, the functional virus proteins cannot form and the virus cannot replicate and assemble. Any compound that inhibits the 3CLpro is therefore a potential drug to end the pandemic. Here we show that the diffraction power of 3CLpro crystals is effectively destroyed by Ebselen. It appears that Ebselen may be a widely available, relatively cost effective way to eliminate the SARS coronavirus 2.

to the active center was observed. They all constitute a database of potential drugs to target the 23 3CLpro. Apart from the fragments, the most promising compounds are the α-ketoamides (Fig. 1) 24 which bind tightly to the 3CLpro 1-3 . As they are complicated to synthesize they carry a hefty price Figure 1 . SARS CoV-2 3CLpro in its functional, dimeric form 1 . The two subunits A and B are shown in dark and light blue. An α-ketoamide inhibitor is bound to the active site (red box, enlarged). The His-41/Cys-145 catalytic dyad is marked. expensive, but also less known compound that binds to the 3CLpro is Ebselen 4 . Ebselen is a 27 selenium compound (Scheme 1) currently tested for a number of diseases such as bipolar disorder 28 and hearing loss 4 . Selenium is an essential metal, but toxic in higher doses. Ebselen has been shown 29 to bind strongly to the CoV-2 3CLpro 4 , but the structure of the complex is unknown. Here we

show what happens when Ebselen is added to 3CLpro crystals.

Methods.

Expression. The CoV-2 3CLpro sequence was 

After 2 days of soaking, the crystals 81 completely maintained their morphology (Fig. 2b) . fully remote due to restriction of the COVID-19 pandemic. Fig. 2 shows a comparison of 87 diffraction patterns collected from untreated crystals (Fig. 2a) , and crystals treated with the Ebselen 88 (Fig. 2b) . As the untreated crystals diffracted beyond 2 Å, the treated crystals did not show any Bragg reflections whatsoever, even at lowest resolution. They are completely amorphous, despite the nice crystal-like shape. Accordingly, the structure of only the untreated 3CLpro can be solved. RMSD to 6WQF 7 0.39 +/-0.53 Å *last resolution shell in brackets integration of data reduction and structure solution -from diffraction images to an initial 

Structural plasticity of SARS-CoV-2 3CL M-pro active site cavity structures

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