Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide.

[NNadir]

The paper I'll reference is this one: Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved ?-ketoamide inhibitors (Linlin Zhang1,2, Daizong Lin1,3, Xinyuanyuan Sun1,2, Ute Curth4, Christian Drosten5, Lucie Sauerhering6,7, Stephan Becker6,7, Katharina Rox8,9, Rolf Hilgenfeld, Science 20 Mar 2020: eabb3405)

The world's scientific publishing community, in recognition of the crisis affecting all humanity, has made all Covid-19 related papers open sourced.

Here's an excerpt any way, and a few comments on the picture below:

In December 2019, a new coronavirus caused an outbreak of pulmonary disease in the city of Wuhan, the capital of Hubei province in China, and has since spread globally (1, 2). The virus has been named SARS-CoV-2 (3), because the RNA genome is about 82% identical to the SARS coronavirus (SARS-CoV); both viruses belong to clade b of the genus Betacoronavirus (1, 2). The disease caused by SARS-CoV-2 is called COVID-19. Whereas at the beginning of the outbreak, cases were connected to the Huanan seafood and animal market in Wuhan, efficient human-to-human transmission led to exponential growth in the number of cases. On March 11, the World Health Organization (WHO) declared the outbreak a pandemic. As of March 15, there are >170,000 cumulative cases globally, with a ~3.7% case-fatality rate .

One of the best characterized drug targets among coronaviruses is the main protease (Mpro, also called 3CLpro) (4). Along with the papain-like protease(s), this enzyme is essential for processing the polyproteins that are translated from the viral RNA (5). The Mpro operates at no less than 11 cleavage sites on the large polyprotein 1ab (replicase 1ab, ~790 kDa); the recognition sequence at most sites is Leu-Gln? Ser,Ala,Gly) (? marks the cleavage site). Inhibiting the activity of this enzyme would block viral replication. Since no human proteases with a similar cleavage specificity are known, inhibitors are unlikely to be toxic.

Previously, we designed and synthesized peptidomimetic ?-ketoamides as broad-spectrum inhibitors of the main proteases of betacoronaviruses and alphacoronaviruses as well as the 3C proteases of enteroviruses (6). The best of these compounds (11r; Fig. 1) showed an EC50 of 400 picomolar against MERS-CoV in Huh7 cells as well as low micromolar EC50 values against SARS-CoV and a whole range of enteroviruses in various cell lines, although the antiviral activity seemed to depend to a great extent on the cell type used in the experiments (6). In order to improve the half-life of the compound in plasma, we modified 11r by hiding the P3 - P2 amide bond within a pyridone ring (Fig. 1, green circles), in the expectation that this might prevent cellular proteases from accessing this bond and cleaving it. Further, to increase the solubility of the compound in plasma and to reduce its binding to plasma proteins, we replaced the hydrophobic cinnamoyl moiety by the somewhat less hydrophobic Boc group (Fig. 1, red circles) to give 13a (see scheme S1 for synthesis).

Figure 1:



The caption:

Fig. 1 Chemical structures of ?-ketoamide inhibitors 11r, 13a, 13b, and 14b. Colored circles highlight the modifications from one development step to the next (see text).

These test compounds are in a class known as "peptidomimetics." That is they are designed to approximate the shape of peptides without actually being peptides. (Formally all of them have one peptide bond, but none of the structures represent a codon natural amino acid. In two of the structures a precursor has been made by hydrogenating the natural amino acid phenylalanine.

In general, an antiviral drug must be designed to cross a membrane, and thus it is necessary to avoid structures that can ionize wherever possible. It must also possess some "lipophilicity" - a liking for lipids, the main constituents of fats. (An oral drug may have to cross more than one or more membranes.) For many peptide drugs this is done by cyclization; here it is done by chemical modification.)

With the due lack of respect due the orange moron, there is a lot between here and a viable drug. (The multistep chemical sequence can be found in the supplementary material: Doing these sorts of thing on an industrial, rather than a lab, scale is a huge chemical engineering challenge in itself.)

But the good news, in viral drug design, we have tools we have never had before and our pharmaceutical scientists, learning from the days of AIDS, are a damned powerful rapid response team.

[Wellstone ruled]

1. Thanks for the background Article.

Read a real short summary in the Guardian Eourpe Edition a few days back,thanks for publishing the Sequence Diagrams. Again,it is hygiene that will win over the day until such time we see a Vaccine maybe with in a year.

[NNadir]

2. You're welcome. This is not a vaccine however; it's a treatment. n/t.

[Wellstone ruled]

3. That I understand.

From this treatment comes vaccine trials . Amazing how the US press is so friggin clueless only too cowtow to the Orange Anus,while Eourpe and Asia are identifying just what this SAR's 2.0 is,and mapping its Genome as well as identifying the attack points within the Human Body.

Our Media is doing nothing but giving Trump a reelection Platform similiar to four years ago.