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2.
Organic process research & development ; 2023.
Article in English | Europe PMC | ID: covidwho-2238569

ABSTRACT

Lufotrelvir was designed as a first in class 3CL protease inhibitor to treat COVID-19. Development of lufotrelvir was challenged by its relatively poor stability due to its propensity to epimerize and degrade. Key elements of process development included improvement of the supply routes to the indole and lactam fragments, a Claisen addition to homologate the lactam, and a subsequent phosphorylation reaction to prepare the prodrug as well as identification of a DMSO solvated form of lufotrelvir to enable long-term storage. As a new approach to preparing the indole fragment, a Cu-catalyzed C–O coupling using oxalamide ligands was demonstrated. The control of process-related impurities was essential to accommodate the parenteral formulation. Isolation of an MEK solvate followed by the DMSO solvate ensured that all impurities were controlled appropriately.

3.
Front Pharmacol ; 13: 1029093, 2022.
Article in English | MEDLINE | ID: covidwho-2199110

ABSTRACT

The translation initiation complex 4F (eIF4F) is a rate-limiting factor in protein synthesis. Alterations in eIF4F activity are linked to several diseases, including cancer and infectious diseases. To this end, coronaviruses require eIF4F complex activity to produce proteins essential for their life cycle. Efforts to target coronaviruses by abrogating translation have been largely limited to repurposing existing eIF4F complex inhibitors. Here, we report the results of a high throughput screen to identify small molecules that disrupt eIF4F complex formation and inhibit coronavirus RNA and protein levels. Of 338,000 small molecules screened for inhibition of the eIF4F-driven, CAP-dependent translation, we identified SBI-1232 and two structurally related analogs, SBI-5844 and SBI-0498, that inhibit human coronavirus OC43 (HCoV-OC43; OC43) with minimal cell toxicity. Notably, gene expression changes after OC43 infection of Vero E6 or A549 cells were effectively reverted upon treatment with SBI-5844 or SBI-0498. Moreover, SBI-5844 or SBI-0498 treatment effectively impeded the eIF4F complex assembly, with concomitant inhibition of newly synthesized OC43 nucleocapsid protein and OC43 RNA and protein levels. Overall, we identify SBI-5844 and SBI-0498 as small molecules targeting the eIF4F complex that may limit coronavirus transcripts and proteins, thereby representing a basis for developing novel therapeutic modalities against coronaviruses.

4.
Aesthet Surg J ; 42(3): 314-324, 2022 02 15.
Article in English | MEDLINE | ID: covidwho-1405004

ABSTRACT

Preoperative assessment of a potential surgical patient has long been a cornerstone of patient safety. As more patients get, and recover from, COVID, plastic surgeons will be faced with the challenge of evaluating the health status and operative risk of convalescent COVID patients who now desire elective surgery. A significant fraction of these patients, however, can have new or persistent health issues as a result of COVID-19, which can affect surgical safety. This paper briefly examines the current relevant literature regarding the post-COVID patient, reviews the waiting period for adequate recovery, and suggests an evidence-based framework for preoperative assessment, based on the severity of the prior COVID-19 episode, ongoing symptoms, and basic screening tests.


Subject(s)
COVID-19 , Plastic Surgery Procedures , Surgery, Plastic , Elective Surgical Procedures , Humans , SARS-CoV-2
5.
Aesthet Surg J ; 41(1): 98-108, 2021 01 01.
Article in English | MEDLINE | ID: covidwho-998281

ABSTRACT

BACKGROUND: A moratorium was placed on nonurgent surgery throughout much of the United States in mid-March 2020 due to surging numbers of COVID-19 cases. Several months later, and with new safety precautions in place, elective surgery gradually resumed. However, no data exist on the safety of plastic surgery during the pandemic. OBJECTIVES: This aim of this survey was to assess the safety of plastic surgery during the pandemic by quantifying: (1) the preoperative prevalence of SARS-CoV-2; (2) the risk of postoperative COVID-19; (3) outcomes and precious resource utilization for such cases; and (4) the risks to office staff. METHODS: Los Angeles plastic surgeons certified by the American Board of Plastic Surgery (ABPS) were sent an online survey in July 2020, during a local COVID-19 surge, querying about the number of procedures performed in the 8- to 10-week period since reopening, testing policies, surgical complications, and cases among staff. RESULTS: In total, 112 surgeons reported 5633 surgeries since resuming elective surgery. Of these, 103 (91.96%) surgeons obtained a preoperative SARS-CoV-2 polymerase chain reaction (PCR) test for every patient. The preoperative PCR test was positive in 41/5881 (0.69%). Positive tests within 2 weeks postoperation occurred in 7/5380 (0.13%) of surgical patients, 3/8506 (0.04%) of injection patients, and 6/2519 (0.24%) of energy therapy patients. Nine offices reported at least 1 staff member who developed COVID-19. All cases were mild, with no hospitalizations or deaths. CONCLUSIONS: These data demonstrate that plastic surgery can be performed safely during a COVID-19 surge by ABPS diplomates. This has profound impact for patients, plastic surgeons, and health policy regulators.


Subject(s)
COVID-19 , Surgery, Plastic , Elective Surgical Procedures , Humans , Los Angeles/epidemiology , Outpatients , SARS-CoV-2 , Surgery, Plastic/adverse effects , Surveys and Questionnaires
6.
Aesthet Surg J Open Forum ; 2(2): ojaa017, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-913156
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