ABSTRACT
Vaccines and first-generation antiviral therapeutics have provided important protection against coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there remains a need for additional therapeutic options that provide enhanced efficacy and protection against potential viral resistance. The SARS-CoV-2 papain-like protease (PLpro) is one of two essential cysteine proteases involved in viral replication. While inhibitors of the SARS-CoV-2 main protease (Mpro) have demonstrated clinical efficacy, known PLpro inhibitors have to date lacked the inhibitory potency and requisite pharmacokinetics to demonstrate that targeting PLpro translates to in vivo efficacy in a preclinical setting. Herein, we report the machine learning-driven discovery of potent, selective, and orally available SARS-CoV-2 PLpro inhibitors, with lead compound PF-07957472 (4) providing robust efficacy in a mouse-adapted model of COVID-19 infection.
Subject(s)
COVID-19 , Coronavirus InfectionsABSTRACT
During 2019, the number of patients suffering from cough, fever and reduction of WBC’s count increased. At the beginning, this mysterious illness was called “fever with unknown origin”. At the present time, the cause of this pneumonia is known as the 2019 novel coronavirus (2019-nCoV) or the severe acute respiratory syndrome corona virus 2 (SARS-CoV-2). The SARS-CoV-2 is one member of great family of coronaviruses. Coronaviruses can cause different kind of illnesses including respiratory, enteric, hepatic, and neurological diseases in animals like cat and bat. Coronaviruses are enveloped positive-stranded RNA viruses. The SARS-CoV-2 has some particular structures for binding to host cells, reproducing itself in cells and damaging human cells. The SARS-CoV-2 can bind angiotensin-converting enzyme 2 (ACE‐2) receptors and cause various difficulties for human. The SARS-CoV-2 can cause either not-serious issues like fever and cough or serious concerns such as multi-organ failure. Source(s) of SARS-CoV-2 is under debate. Malayan pangolin and bat are the most suspicious candidate for being sources of the SARS-CoV-2. The SARS-CoV-2 can be transmitted by various ways such as transmitting from infected human to healthy human and can make severe pneumonia, which can lead to death. The SARS-CoV-2 can infect different kind of people with different ages, races, and social and economic levels. The SARS‐CoV‐2 infection can cause various sorts of clinical manifestations like cough and fever and intensity of signs and symptoms depends on sufferer conditions. Clinicians use all of available documents and tests like laboratory, histopathological and radiological findings for diagnosing new cases and curing patients with high accuracy. At the present time, there is no particular way for treating SARS-CoV-2 infection; neither antiviral drugs nor palliative agents. It seems that the best way for standing against the SARS-CoV-2 infection is preventing from it by social distancing and vaccination. This review tries to prepare an essential brief update about SARS-CoV-2 infection for clinicians.
Subject(s)
Multiple Organ Failure , Fever , Pneumonia , Cough , Severe Acute Respiratory Syndrome , Heredodegenerative Disorders, Nervous System , COVID-19 , Respiratory InsufficiencyABSTRACT
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 is rapidly spreading worldwide. Scientists are searching to find an effective treatment for coronavirus disease 2019 (COVID-19). Several antiviral drugs are currently undergoing clinical trial studies to evaluate their safety and efficacy in the treatment of COVID-19. SARS-CoV-2 is a positive-sense single-stranded RNA virus. Previous studies showed the efficacy of anti-RNA virus, single strand RNA inhibiting antisense RNAs (asRNAs), on silencing of virus replication, in vitro. To transfer the anti-SARS-CoV-2 asRNAs to human respiratory epithelium, exosomes can be suggested as a promising candidate. Mesenchymal stem cells (MSCs) secret exosomes and they can be loaded by anti-RNA virus asRNAs. MSCs-secreted exosomes as a nano-cargo of anti-SARS-CoV-2 asRNAs have other therapeutic potentials such as immunomodulatory effects of their cytokine contents, affinity to respiratory epithelial attachment, anti-fibrotic activity in lung, non-toxicity for normal cells, and do not trigger an immune response. Inhalation of anti-SARS-CoV-2 asRNAs may stop SARS-CoV-2 replication. Producing a specific anti-SARS-CoV-2 asRNAs by targeting the genome of virus and their delivery by MSCs exosomes is suggested and discussed. This approach potentially sheds light on gene therapy of the other human lung diseases via inhalational delivery using exosomes in future.