X-ray Structure of Main Protease of the Novel Coronavirus SARS-CoV-2 Enables Design of α-Ketoamide Inhibitors

AbstractA novel coronavirus has been identified as the causative agent of a massive outbreak of atypical pneumonia originating at Wuhan, Hubei province, China. Involved in the formation of the coronavirus replication complex, the viral main protease (Mpro, also called 3CLpro) represents an attractive target for therapy. We determined the crystal structure of the unliganded Mpro at 1.75 Å resolution and used this structure to guide optimization of a series of alpha-ketoamide inhibitors. The main goal of the optimization efforts was improvement of the pharmacokinetic properties of the compounds. We further describe 1.95- and 2.20-Å crystal structures of the complex between the enzyme and the most potent alpha-ketoamide optimized this way. These structures will form the basis for further development of these compounds to antiviral drugs.

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Chemistry and Crystal Structures of Some Constituents of Zingiber cassumunar

Australian Journal of Chemistry ◽

10.1071/ch9790071 ◽

1979 ◽

Vol 32 (1) ◽

pp. 71 ◽

Cited By ~ 29

Author(s):

T Amatayakul ◽

J Cannon ◽

P Dampawan ◽

T Dechatiwongse ◽

RF Giles ◽

...

Keyword(s):

Crystal Structure ◽

Least Squares ◽

Crystal Structures ◽

Structure Determination ◽

Aromatic Compounds ◽

Crystal Structure Determination ◽

The Novel ◽

X Ray ◽

Zingiber Cassumunar ◽

Block Diagonal

The novel aromatic compounds cis-3-(2',4',5'-trimethoxyphenyl)-4-[(E)-2''',4''',5'''-trimethoxy-styryl]cyclohex-1-ene(1), cis-3-(3',4'-dimethoxyphenyl)-4-[(E)-3''',4'''-dimethoxystyryl]cyclohex-1-ene (2), a substance assigned the tentative structure cis-3-(3',4'-dimethoxyphenyl)-4-[(E)-2''',4''',5'''- trimethoxystyryl]cyclohex-1-ene (3),(E)-4-(3',4'-dimethoxypheny1)but-3-en-1-ol (5), (E)-4-(3',4'-dimethoxypheny1)but-3-en-1-yl acetate (6), and 8-(3',4'-dimethoxyphenyl)-2-methoxynaphtho-1,4- quinone (7) have been isolated from the rhizomes of Zingiber cassurnunav Roxb. (Zingiberaceae). The crystal structures of the cyclohexene derivative (1) and the quinone (7) have been determined from X-ray diffractometer data at 295 K and refined by block diagonal least squares to residuals of 0.046 (2099 'observed' reflections) and 0.093 (1246), respectively. Crystals of compound (1) are triclinic, P1, a 18.027(12), b 10.037(9), c 6.530(5) α, 84.22 (7), β 81.87 (6), γ 85.72 (6)�, Z 2. Crystals of the quinone (7) are monoclinic, P21/a, a 22.89 (1), b 8.022 (5), c 8.458 (5) �, β 91.98 (5)�, Z 4. Although the latter crystal structure determination is imprecise, due largely to the very small size of the crystal available, the solution is unambiguous. A simple two-step synthesis of the quinone (7) has been achieved.

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Identification of SARS-CoV2 Main Protease Coldspots Suitable for Drug Targeting

10.21203/rs.3.rs-123804/v1 ◽

2020 ◽

Author(s):

Navaneethakrishnan Krishnamoorthy ◽

Khalid Fakhro

Keyword(s):

Active Site ◽

Missense Mutations ◽

The Novel ◽

X Ray ◽

X Ray Crystallography ◽

Main Protease ◽

New Perspective ◽

Function Relationship ◽

Novel Coronavirus ◽

Relationship Of

Abstract Most attempts to target the novel coronavirus SARS-CoV2 are focusing on the main protease (Mpro) 1,2. We already have access to high resolution 3D-structures of the SARS-CoV2 Mpro, which were developed with inhibitors as co-crystals using X-ray crystallography 3-9. However, >19,000 missense mutations in the Mpro have already been reported 10. The mutations encompassing 282 amino acid positions and these “hotspots” might change the Mpro structure and activity, potentially rendering novel antivirals and vaccines ineffective. Here we identified 24 mutational “coldspots” that have resisted mutation since the virus was first detected. We compared the structure-function relationship of these coldspots with several SARS-CoV2 Mpro X-ray crystal structures. We found that three coldspot residues (Leu141, Phe185 and Gln192) help to form the active site, while six (Gly2, Arg4, Tyr126, Lys137, Leu141 and Leu286) contribute to dimer formation that is required for Mpro activity. Importantly, seven coldpots are conserved among other coronaviruses and available on the surface of the active site and at the dimer interface for targeting. The identification and short list of these coldspots offers a new perspective to target the SARS-CoV2 Mpro while avoiding mutation-based drug resistance.

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Identification of Mutation Resistance Coldspots for Targeting the SARS-CoV2 Main Protease

10.21203/rs.3.rs-123804/v3 ◽

2020 ◽

Author(s):

Navaneethakrishnan Krishnamoorthy ◽

Khalid Fakhro

Keyword(s):

Active Site ◽

The Novel ◽

Dimer Interface ◽

X Ray ◽

Main Protease ◽

New Perspective ◽

Function Relationship ◽

Novel Coronavirus ◽

Relationship Of ◽

Structure And Activity

Abstract Most attempts to target the novel coronavirus SARS-CoV2 are focusing on the main protease (Mpro) 1-9. However, >19,000 mutations in the Mpro have already been reported 10. The mutations encompassing 282 amino acid positions and these “hotspots” might change the Mpro structure and activity, potentially rendering novel antivirals and vaccines ineffective. Here we identified 24 mutational “coldspots” that have resisted mutation since the virus was first detected. We compared the structure-function relationship of these coldspots with several SARS-CoV2 Mpro X-ray crystal structures. We found that three coldspot residues (Leu141, Phe185 and Gln192) help to form the active site, while six (Gly2, Arg4, Tyr126, Lys137, Leu141 and Leu286) contribute to dimer formation that is required for Mpro activity. The surface of the dimer interface is more resistant to mutations compared to the active site. Interestingly, 16 coldspots are found in conserved patterns when compared with other coronaviruses. Importantly, several conserved coldpots are available on the surface of the active site and at the dimer interface for targeting. The identification and short list of these coldspots offers a new perspective to target the SARS-CoV2 Mpro while avoiding mutation-based drug resistance.

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Comparative docking of SARS-CoV-2 receptors antagonists from repurposing drugs

10.26434/chemrxiv.12044538.v4 ◽

2020 ◽

Author(s):

Micael Davi Lima de Oliveira ◽

Kelson Mota Teixeira de Oliveira

Keyword(s):

World Health Organisation ◽

World Health ◽

Lung Cells ◽

The Novel ◽

High Modulation ◽

Main Protease ◽

The World ◽

Novel Coronavirus ◽

Viral Receptors ◽

Theoretical Results

According to the World Health Organisation, until 16 June, 2020, the number of confirmed and notified cases of COVID-19 has already exceeded 7.9 million with approximately 434 thousand deaths worldwide. This research aimed to find repurposing antagonists, that may inhibit the activity of the main protease (Mpro) of the SARS-CoV-2 virus, as well as partially modulate the ACE2 receptors largely found in lung cells, and reduce viral replication by inhibiting Nsp12 RNA polymerase. Docking molecular simulations were performed among a total of 60 structures, most of all, published in the literature against the novel coronavirus. The theoretical results indicated that, in comparative terms, paritaprevir, ivermectin, ledipasvir, and simeprevir, are among the most theoretical promising drugs in remission of symptoms from the disease. Furthermore, also corroborate indinavir to the high modulation in viral receptors. The second group of promising drugs includes remdesivir and azithromycin. The repurposing drugs HCQ and chloroquine were not effective in comparative terms to other drugs, as monotherapies, against SARS-CoV-2 infection.

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Crystal Chemical Relations in the Shchurovskyite Family: Synthesis and Crystal Structures of K2Cu[Cu3O]2(PO4)4 and K2.35Cu0.825[Cu3O]2(PO4)4

Crystals ◽

10.3390/cryst11070807 ◽

2021 ◽

Vol 11 (7) ◽

pp. 807

Author(s):

Ilya V. Kornyakov ◽

Sergey V. Krivovichev

Keyword(s):

Crystal Structure ◽

Crystal Structures ◽

Structural Complexity ◽

Crystal Chemical ◽

X Ray Diffraction ◽

Complexity Measures ◽

X Ray ◽

The Family ◽

Similarities And Differences ◽

Related Compounds

Single crystals of two novel shchurovskyite-related compounds, K2Cu[Cu3O]2(PO4)4 (1) and K2.35Cu0.825[Cu3O]2(PO4)4 (2), were synthesized by crystallization from gaseous phase and structurally characterized using single-crystal X-ray diffraction analysis. The crystal structures of both compounds are based upon similar Cu-based layers, formed by rods of the [O2Cu6] dimers of oxocentered (OCu4) tetrahedra. The topologies of the layers show both similarities and differences from the shchurovskyite-type layers. The layers are connected in different fashions via additional Cu atoms located in the interlayer, in contrast to shchurovskyite, where the layers are linked by Ca2+ cations. The structures of the shchurovskyite family are characterized using information-based structural complexity measures, which demonstrate that the crystal structure of 1 is the simplest one, whereas that of 2 is the most complex in the family.

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Some Novel Cobalt Diphenylphosphine Complexes: Synthesis, Characterization, and Behavior in the Polymerization of 1,3-Butadiene

Molecules ◽

10.3390/molecules26134067 ◽

2021 ◽

Vol 26 (13) ◽

pp. 4067

Author(s):

Giovanni Ricci ◽

Giuseppe Leone ◽

Giorgia Zanchin ◽

Benedetta Palucci ◽

Alessandra Forni ◽

...

Keyword(s):

Crystal Structure ◽

Single Crystals ◽

The Novel ◽

X Ray Diffraction ◽

X Ray ◽

And Behavior

Some novel cobalt diphenylphosphine complexes were synthesized by reacting cobalt(II) chloride with (2-methoxyethyl)diphenylphosphine, (2-methoxyphenyl)diphenylphosphine, and 2-(1,1-dimethylpropyl)-6-(diphenylphosphino)pyridine. Single crystals suitable for X-ray diffraction studies were obtained for the first two complexes, and their crystal structure was determined. The novel compounds were then used in association with methylaluminoxane (MAO) for the polymerization of 1,3-butadiene, and their behavior was compared with that exhibited in the polymerization of the same monomer by the systems CoCl2(PnPrPh2)2/MAO and CoCl2(PPh3)2/MAO. Some significant differences were observed depending on the MAO/Co ratio used, and a plausible interpretation for such a different behavior is proposed.

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Atypical respiratory distress in eastern Democratic Republic of the Congo prior to the COVID-19 pandemic. A case report

Tropical Diseases Travel Medicine and Vaccines ◽

10.1186/s40794-021-00134-6 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Guy-Quesney Mateso ◽

Marius Baguma ◽

Pacifique Mwene-Batu ◽

Ghislain Maheshe Balemba ◽

Fabrice Nzabara ◽

...

Keyword(s):

Respiratory Distress ◽

Democratic Republic ◽

Atypical Pneumonia ◽

The Novel ◽

Republic Of The Congo ◽

Chest X Ray ◽

Novel Coronavirus ◽

Laboratory Changes ◽

Official Declaration ◽

Ray Series

Abstract Background Predictions have been made that Africa would be the most vulnerable continent to the novel Coronavirus disease 2019 (COVID-19). Interestingly, the spread of the disease in Africa seems to have been delayed and initially slower than in many parts of the world. Here we report on two cases of respiratory distress in our region before the official declaration of the disease in December 2019, cases which in the present times would be suspect of COVID-19. Case presentation These two cases (one 55-year-old man and one 25-year-old woman) of acute respiratory distress secondary to atypical pneumonia were seen in Bukavu, in Eastern Democratic Republic of the Congo (DRC), between September and December 2019. One patient had returned from China and the other had close contacts with travellers from China in the 2 weeks prior to the onset of symptoms. In either case, the aetiology could not be accurately determined. However, the two cases presented a clinical picture (progressive dyspnoea, preceded by dry cough and fever) and laboratory changes (procalcitonin within the normal range, slight inflammation, and lymphopenia) compatible with a viral infection. The chest X-ray series of the first patient showed lesions (reticulations, ground glass, and nodules ≤6 mm) similar to those currently found in COVID-19 patients. In addition, unlike the 25-year-old female patient who had no comorbidity, the 55-year-old male patient who had hypertension as comorbidity, developed a more severe acute respiratory distress which progressed to death. Conclusion These cases bring to the attention the fact that COVID-19-like syndromes may have already been present in the region months before the official beginning of the pandemic. This also brings to question whether a prior presence of the disease or infections with related virus may account for the delayed and less extensive development of the pandemic in the region.

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