Production of Proteins of the SARS-CoV-2 Proteome for Drug Discovery

Kim, Choon; Mahasenan, Kiran V.; Bhardwaj, A.; Wiest, Olaf; Chang, Mayland; Mobashery, Shahriar

doi:10.1021/acsomega.1c02984

Cited by 11 publications

(7 citation statements)

References 78 publications

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“…The genes were PCR amplified from the strain C. difficile 630. Restriction digestion and ligation into the vector pETHST [22] allowed for expression of the genes fused with 6×His‐ and Twin‐Strep‐tags at the N ‐terminus of the proteins in the E. coli LOBSTR‐RIL background. The constructs allowed for overproduction of the three proteins, which also included formation of inclusion bodies.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Muramyl‐δ‐Lactam in Spore Peptidoglycan of Clostridioides difficile

et al. 2023

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Clostridioides difficile is a spore‐forming human pathogen responsible for significant morbidity and mortality. Infections by this pathogen ensue dysbiosis of the intestinal tract, which leads to germination of the spores. The process of spore formation requires a transition for the cell‐wall peptidoglycan of the vegetative C. difficile to that of spores, which entails the formation of muramyl‐δ‐lactam. We describe a set of reactions for three recombinant C. difficile proteins, GerS, CwlD, and PdaA1, with the use of four synthetic peptidoglycan analogs. CwlD and PdaA1 excise the peptidoglycan stem peptide and the acetyl moiety of N‐acetyl muramate, respectively. The reaction of CwlD is accelerated in the presence of GerS. With the use of a suitable substrate, we document that PdaA1 catalyzes a novel zinc‐dependent transamidation/transpeptidation reaction, an unusual reaction that requires excision of the stem peptide as a pre‐requisite.

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Section: Resultsmentioning

confidence: 99%

Synthesis of Muramyl‐δ‐Lactam in Spore Peptidoglycan of Clostridioides difficile

et al. 2023

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“…Cyclocurcumin, Bisdemethoxycurcumin, and Demethoxycurcumin were found to exhibit high affinity with SARS-CoV-2 ADP ribose phosphatase, NSP3 (Maurya and Sharma, 2020). The binding of these phytochemicals with NSP3 may slow down the cleavage of PPs to release NSPs and decrease the process of viral replication and transcription (Kim, et al, 2021). the predicted binding energy of different phytochemicals with molecules involved in the inflammatory processes such as COX2, PLA2, NIK, and IRAK-4 show that Cyclocurcumin may possess a high binding affinity with most of the inflammatory molecules (Maurya and Sharma, 2020).…”

Section: Discussionmentioning

confidence: 99%

Antiviral Activitiy of Curcumin, Demethoxycurcumin, Bisdemethoxycurcumin and Cyclocurcumin compounds of Curcuma longa against NSP3 on SARS-CoV-2

Hidayah

Nafisa

'Arifin

et al. 2023

Indones J Cancer Chemoprevent

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SARS-CoV-2 genome encodes two large polyproteins (pp), pp1a and pp1ab which are cleaved and transformed into a mature form by a protease, non-structural protein 3 (NSP3). NSP3 is encoded by open reading frame (ORF) 1a/b. Curcuma longa (C. longa) or turmeric has been documented to have antiviral effects. The aim of this study was to assess the viral activities of C. longa against SARS-CoV-2 focusing on its potency to inhibit viral replication by targeting NSP3. PubChem databases were used to obtain the metabolic profile of C. longa. The compound's interaction with nucleocapsid was analyzed using molecular docking with Molegro Virtual Docker. Bioinformatics analysis based on rerank score presents all compounds of C. longa have higher binding affinity than the native ligand with cyclocurcumin as the lowest score (-128.38 kcal/mol). This anti-viral activity was hypothesized from the similarity of hydrogen bonds with amino acid residues Ser 128 and Asn 40 as key residues present in Ribavirin. This study reveals that C. longa is the potential to be developed as an antiviral agent through replication inhibition in SARS-CoV-2 targeting its replication mediated by NSP3.Keywords: C. longa, Non-Structural Protein 3, COVID-19.

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“…The full-length SleC and CspC were labeled with a fluorescent reported (for MST analysis) by a procedure described previously by us for an unrelated system ( 35 ).…”

Section: Methodsmentioning

confidence: 99%

A dual-action antibiotic that kills Clostridioides difficile vegetative cells and inhibits spore germination

Janardhanan

Kim

Qian

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Clostridioides difficile infection (CDI) is the most lethal of the five CDC urgent public health treats, resulting in 12,800 annual deaths in the United States alone [ Antibiotic Resistance Threats in the United States, 2019 (2019), www.cdc.gov/DrugResistance/Biggest-Threats.html ]. The high recurrence rate and the inability of antibiotics to treat such infections mandate discovery of new therapeutics. A major challenge with CDI is the production of spores, leading to multiple recurrences of infection in 25% of patients [C. P. Kelly, J. T. LaMont, N. Engl. J. Med. 359 , 1932–1940 (2008)], with potentially lethal consequence. Herein, we describe the discovery of an oxadiazole as a bactericidal anti- C. difficile agent that inhibits both cell-wall peptidoglycan biosynthesis and spore germination. We document that the oxadiazole binds to the lytic transglycosylase SleC and the pseudoprotease CspC for prevention of spore germination. SleC degrades the cortex peptidoglycan, a critical step in the initiation of spore germination. CspC senses germinants and cogerminants. Binding to SleC is with higher affinity than that to CspC. Prevention of spore germination breaks the nefarious cycles of CDI recurrence in the face of the antibiotic challenge, which is a primary cause of therapeutic failure. The oxadiazole exhibits efficacy in a mouse model of recurrent CDI and holds promise in clinical treatment of CDI.

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Production of Proteins of the SARS-CoV-2 Proteome for Drug Discovery

Cited by 11 publications

References 78 publications

Synthesis of Muramyl‐δ‐Lactam in Spore Peptidoglycan of Clostridioides difficile

Synthesis of Muramyl‐δ‐Lactam in Spore Peptidoglycan of Clostridioides difficile

Antiviral Activitiy of Curcumin, Demethoxycurcumin, Bisdemethoxycurcumin and Cyclocurcumin compounds of Curcuma longa against NSP3 on SARS-CoV-2

A dual-action antibiotic that kills Clostridioides difficile vegetative cells and inhibits spore germination

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