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      Design and Evaluation of a Novel Peptide–Drug Conjugate Covalently Targeting SARS-CoV-2 Papain-like Protease

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          Abstract

          Coronavirus disease 2019 (COVID-19) pandemic, a global health threat, was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The SARS-CoV-2 papain-like cysteine protease (PLpro) was recognized as a promising drug target because of multiple functions in virus maturation and antiviral immune responses. Inhibitor GRL0617 occupied the interferon-stimulated gene 15 (ISG15) C-terminus-binding pocket and showed an effective antiviral inhibition. Here, we described a novel peptide–drug conjugate (PDC), in which GRL0617 was linked to a sulfonium-tethered peptide derived from PLpro-specific substrate LRGG. The EM-C and EC-M PDCs showed a promising in vitro IC50 of 7.40 ± 0.37 and 8.63 ± 0.55 μM, respectively. EC-M could covalently label PLpro active site C111 and display anti-ISGylation activities in cellular assays. The results represent the first attempt to design PDCs composed of stabilized peptide inhibitors and GRL0617 to inhibit PLpro. These novel PDCs provide promising opportunities for antiviral drug design.

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          Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

          Chaolin Huang, Yeming Wang, Xingwang Li … (2020)
          Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.
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            Characteristics of SARS-CoV-2 and COVID-19

            Ben Hu, Hua Guo, Peng Zhou … (2020)
            Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible and pathogenic coronavirus that emerged in late 2019 and has caused a pandemic of acute respiratory disease, named ‘coronavirus disease 2019’ (COVID-19), which threatens human health and public safety. In this Review, we describe the basic virology of SARS-CoV-2, including genomic characteristics and receptor use, highlighting its key difference from previously known coronaviruses. We summarize current knowledge of clinical, epidemiological and pathological features of COVID-19, as well as recent progress in animal models and antiviral treatment approaches for SARS-CoV-2 infection. We also discuss the potential wildlife hosts and zoonotic origin of this emerging virus in detail.
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              Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results

              Aldo Pietro Maggioni, Jonathan Sterne (2021)
              Abstract Background World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs — remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a — in patients hospitalized with coronavirus disease 2019 (Covid-19). Methods We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry. Results At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan–Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P=0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P=0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P=0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P=0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration. Conclusions These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.)
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Med Chem
                Journal ID (iso-abbrev): J Med Chem
                Journal ID (publisher-id): jm
                Journal ID (coden): jmcmar
                Title: Journal of Medicinal Chemistry
                Publisher: American Chemical Society
                ISSN (Print): 0022-2623
                ISSN (Electronic): 1520-4804
                Publication date (Electronic): 04 January 2022
                Publication date (Print): 13 January 2022
                Volume: 65
                Issue: 1
                Pages: 876-884
                Affiliations
                [† ]State Key Laboratory of Chemical Oncogenomics, Guangdong Provincial Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School , Shenzhen 518055, China
                [‡ ]Pingshan Translational Medicine Center, Shenzhen Bay Laboratory , Shenzhen 518118, China
                [§ ]Institute for Systems and Physical Biology, Shenzhen Bay Laboratory , Shenzhen, Guangdong 518032, China
                Author notes
                Author information
                https://orcid.org/0000-0003-3830-4133
                https://orcid.org/0000-0002-9958-5699
                https://orcid.org/0000-0002-3630-8520
                Article
                DOI: 10.1021/acs.jmedchem.1c02022
                PMC ID: 8753845
                PubMed ID: 34981929
                SO-VID: 6131887f-1128-4027-ad95-9075f982eea5
                Copyright © © 2022 American Chemical Society
                License:

                This article is made available via the PMC Open Access Subset for unrestricted RESEARCH re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                Date received : 24 November 2021
                Funding
                Funded by: National Natural Science Foundation of China, doi 10.13039/501100001809;
                Award ID: 21778009
                Funded by: Shenzhen Bay Laboratory, doi NA;
                Award ID: S201101001
                Funded by: Shenzhen Bay Laboratory, doi NA;
                Award ID: SZBL2021080601010
                Funded by: Shenzhen Science and Technology Innovation Committee, doi NA;
                Award ID: RCJC20200714114433053
                Funded by: Shenzhen Science and Technology Innovation Committee, doi NA;
                Award ID: JCYJ20200109140406047
                Funded by: Shenzhen Science and Technology Innovation Committee, doi NA;
                Award ID: JCYJ201805081522131455
                Funded by: Beijing National Laboratory of Molecular Science, doi NA;
                Award ID: BNLMS20160112
                Funded by: Shenzhen-Hong Kong Institute of Brain Science, doi 10.13039/501100019404;
                Award ID: 2019SHIBS0004
                Funded by: Natural Science Foundation of Guangdong Province, doi 10.13039/501100003453;
                Award ID: 2020A1515011544
                Funded by: Natural Science Foundation of Guangdong Province, doi 10.13039/501100003453;
                Award ID: 2020A1515010522
                Funded by: Ministry of Science and Technology of the People''s Republic of China, doi 10.13039/501100002855;
                Award ID: 2018YFA0902504
                Funded by: National Natural Science Foundation of China, doi 10.13039/501100001809;
                Award ID: 21977010
                Categories
                Subject: Article
                Custom metadata
                document-id-old-9 jm1c02022
                document-id-new-14 jm1c02022
                ccc-price

                ScienceOpen disciplines: Pharmaceutical chemistry
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                ScienceOpen disciplines: Pharmaceutical chemistry

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