Viral Proteases as Targets for Coronavirus Disease 2019 Drug Development.
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ABSTRACT:
SUBMITTER: Zhu W
PROVIDER: S-EPMC8686716 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Viral proteases are indispensable for successful virion maturation, thus making them a prominent drug target. Their enzyme activity is tightly spatiotemporally regulated by expression in the precursor form with little or no activity, followed by activation via autoprocessing. These cleavage events are frequently triggered upon transportation to a specific compartment inside the host cell. Typically, precursor oligomerization or the presence of a co-factor is needed for activation. A detailed understanding of these mechanisms will allow ligands with non-canonical mechanisms of action to be designed, which would specifically modulate the initial irreversible steps of viral protease autoactivation. Binding sites exclusive to the precursor, including binding sites beyond the protease domain, can be exploited. Both inhibition and up-regulation of the proteolytic activity of viral proteases can be detrimental for the virus. All these possibilities are discussed using examples of medically relevant viruses including herpesviruses, adenoviruses, retroviruses, picornaviruses, caliciviruses, togaviruses, flaviviruses, and coronaviruses.
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Project description:Some medically important viruses-including retroviruses, flaviviruses, coronaviruses, and herpesviruses-code for a protease, which is indispensable for viral maturation and pathogenesis. Viral protease inhibitors have become an important class of antiviral drugs. Development of the first-in-class viral protease inhibitor saquinavir, which targets HIV protease, started a new era in the treatment of chronic viral diseases. Combining several drugs that target different steps of the viral life cycle enables use of lower doses of individual drugs (and thereby reduction of potential side effects, which frequently occur during long term therapy) and reduces drug-resistance development. Currently, several HIV and HCV protease inhibitors are routinely used in clinical practice. In addition, a drug including an inhibitor of SARS-CoV-2 main protease, nirmatrelvir (co-administered with a pharmacokinetic booster ritonavir as Paxlovid®), was recently authorized for emergency use. This review summarizes the basic features of the proteases of human immunodeficiency virus (HIV), hepatitis C virus (HCV), and SARS-CoV-2 and discusses the properties of their inhibitors in clinical use, as well as development of compounds in the pipeline.
| S-EPMC9706241 | biostudies-literature
Project description:Background: The dawn of the year 2020 witnessed the spread of the highly infectious and communicable disease coronavirus disease 2019 (COVID-19) globally since it was ?rst reported in 2019. Severe acute respiratory syndrome coronavirus-2 is the main causative agent. In total, 3,096,626 cases and 217,896 deaths owing to COVID-19 were reported by 30th April, 2020 by the World Health Organization. This means infection and deaths show an exponential growth globally. In order to tackle this pandemic, it is necessary to ?nd possible easily accessible therapeutic agents till an effective vaccine is developed. Methods: In this study, we present the results of molecular docking processes through high throughput virtual screening to analyze drugs recommended for the treatment of COVID-19. Results: Atovaquone, fexofenadine acetate (Allegra), ethamidindole, baicalin, glycyrrhetic acid, justicidin D, euphol, and curine are few of the lead molecules found after docking 129 known antivirals, antimalarial, antiparasitic drugs and 992 natural products. Conclusions: These molecules could act as an effective inhibitory drug against COVID-19.
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Project description:Objective: To study the potential effect of COVID-19 on the endometrium of affected symptomatic women. Design: Preliminary study of the endometrial transcriptomes in women with COVID-19 through RNA sequencing. Setting: Hospital and university laboratories. Subjects: Women with COVID-19 lacking SARS-CoV-2 infection in endometrial tissue. Intervention/Exposure: Endometrial biopsy collection. Main outcomes measures: Endometrial gene expression and functional analysis of patients with COVID-19 versus uninfected individuals. Results: COVID-19 systemic disease alters endometrial gene expression in 75% of women, with patients exhibiting a preponderance of 163 up-regulated (e.g., UTS2, IFI6, IFIH1, BNIP3) and 72 down-regulated genes (e.g., CPZ, CDH3, IRF4) (FDR<0.05). A total of 161 dysregulated functions (36 up-regulated and 125 down-regulated) were typically enriched in COVID-19 endometria, including upregulation in pathways involved in response to virus and cytokine inflammation, highlighting upregulation of a COVID-19 response pathway. Conclusion: COVID-19 affects endometrial gene expression despite the absence of SARS-CoV-2 particles in endometrial tissues.
2024-04-22 | GSE202553 | GEO
Project description:IntroductionAlzheimer's disease (AD) has few available treatments, and there is a high rate of failure in AD drug development programs. Study of the AD drug development pipeline can provide insight into the evolution of drug development and how best to optimize development practices.MethodsWe reviewed clinicaltrials.gov and identified all pharmacologic AD trials of all agents currently being developed for treatment of AD.ResultsThere are 132 agents in clinical trials for the treatment of AD. Twenty-eight agents are in 42 phase 3 trials; 74 agents are in 83 phase 2 trials; and 30 agents are in 31 phase 1 trials. There is an increase in the number of agents in each phase compared with that in the 2018 pipeline. Nineteen agents in trials target cognitive enhancement, and 14 are intended to treat neuropsychiatric and behavioral symptoms. There are 96 agents in disease modification trials; of these, 38 (40%) have amyloid as the primary target or as one of several effects. Eighteen of the antiamyloid agents are small molecules, and 20 are monoclonal antibodies or biological therapies. Seven small molecules and ten biologics have tau as a primary or combination target (18%). Amyloid is the most common specific target in phase 3 and phase 2 disease modification trials. Novel biomarkers (e.g., neurofilament light), new outcomes (e.g., AD Composite Score [ADCOMS]), enrollment of earlier populations, and innovative trial designs (e.g., Bayesian adaptive designs) are new features in recent clinical trials.DiscussionDrug development continues robustly at all phases despite setbacks in several programs in the recent past. Continuing unmet needs require a commitment to growing and accelerating the pipeline.
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Project description:The present study aimed to uncover the pharmacological function and underlying mechanism of puerarin as a potential treatment for COVID-19, using an in silico methodology, including network pharmacology and molecular docking. The pivotal targets of puerarin to treat COVID-19 were identified and included the epidermal growth factor receptor (EGFR), tumour necrosis factor (TNF), tumour protein p53 (TP53), caspase 3 (CASP3), RELA proto-oncogene (RELA), Fos proto-oncogene (FOS), caspase 8 (CASP8), prostaglandin-endoperoxide synthase 2 (PTGS2), interleukin 2 (IL2), protein kinase CB (PRKCB), B cell lymphoma/leukaemia gene-2 (BCL2), protein kinase CA (PRKCA), nitric oxide synthase 3 (NOS3) and peroxisome proliferator-activated receptor gamma (PPARG). Functionally, the anti-COVID-19 action of puerarin was associated with the suppression of oxidative stress and inflammatory cascades, and cell apoptosis. The signalling pathways of puerarin to treat COVID-19 included modulation of the pathways of apoptosis, IL-17 signalling, mitogen-activated protein kinase (MAPK) signalling and TNF signalling. Molecular docking data illustrated the binding capacity of puerarin with COVID-19 and the effective anti-COVID-19 activity of puerarin. Taken together, our current network pharmacology-based findings revealed the pharmacological role of puerarin in the treatment of COVID-19. Furthermore, the bioinformatic findings elucidated that some of these pivotal targets might serve as potential molecular markers for detecting COVID-19.
| S-EPMC7753316 | biostudies-literature
Project description:Since December 2019, the coronavirus disease 2019 (COVID-19) caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has spread throughout China as well as other countries. More than 8,700,000 confirmed COVID-19 cases have been recorded worldwide so far, with much more cases popping up overseas than those inside. As the initial epicenter in the world, China has been combating the epidemic for a relatively longer period and accumulated valuable experience in prevention and control of COVID-19. This article reviewed the clinical use, mechanism and efficacy of the clinically approved drugs recommended in the Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (DTPNCP) released by National Health Commission of P.R.China, and the novel therapeutic agents now undergoing clinical trials approved by China National Medical Products Administration (NMPA) to evaluate experimental treatment for COVID-19. Reviewing the progress in drug development for the treatment against COVID-19 in China may provide insight into the epidemic control in other countries.
| S-EPMC7319927 | biostudies-literature
Project description:The coronavirus disease 2019 pandemic exposed weaknesses in multiple domains and widened gender-based inequalities across the world. It also stimulated extraordinary scientific achievement by bringing vaccines to the public in less than a year. In this article, we discuss the implications of current vaccination guidance for pregnant and lactating women, if their exclusion from the first wave of vaccine trials was justified, and if a change in the current vaccine development pathway is necessary. Pregnant and lactating women were not included in the initial severe acute respiratory syndrome coronavirus 2 vaccine trials. Therefore, perhaps unsurprisingly, the first vaccine regulatory approvals have been accompanied by inconsistent advice from public health, governmental, and professional authorities around the world. Denying vaccination to women who, although pregnant or breastfeeding, are fully capable of autonomous decision making is a throwback to a paternalistic era. Conversely, lack of evidence generated in a timely manner, upon which to make an informed decision, shifts responsibility from research sponsors and regulators and places the burden of decision making upon the woman and her healthcare advisor. The World Health Organization, the Task Force on Research Specific to Pregnant Women and Lactating Women, and others have highlighted the long-standing disadvantage experienced by women in relation to the development of vaccines and medicines. It is uncertain whether there was sufficient justification for excluding pregnant and lactating women from the initial severe acute respiratory syndrome coronavirus 2 vaccine trials. In future, we recommend that regulators mandate plans that describe the development pathway for new vaccines and medicines that address the needs of women who are pregnant or lactating. These should incorporate, at the outset, a careful consideration of the balance of the risks of exclusion from or inclusion in initial studies, patient and public perspectives, details of "developmental and reproductive toxicity" studies, and approaches to collect data systematically from participants who are unknowingly pregnant at the time of exposure. This requires careful consideration of any previous knowledge about the mode of action of the vaccine and the likelihood of toxicity or teratogenicity. We also support the view that the default position should be a "presumption of inclusion," with exclusion of women who are pregnant or lactating only if justified on specific, not generic, grounds. Finally, we recommend closer coordination across countries with the aim of issuing consistent public health advice.
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Project description:The purpose of this study was to identify miRNAs that were dysregulated after the onset of COVID-19 and thus potentially be used for risk stratification (i.e., mortality). Therefore, we conducted a multi-center, retrospective longitudinal cohort study enrolling 142 patients with laboratory-confirmed SARS-CoV-2 infection who presented to two Canadian hospitals from May 2020 – December 2020 along with a cohort of 27 SARS-CoV-2 patients with mild upper respiratory tract symptoms and 69 SARS-CoV-2-negative patients from the ICU. Blood was biobanked from SARS-CoV-2 positive patients in the emergency department (mild), ward (moderate) or intensive care unit (severe). Assessment of miRNA expression and co-regulatory network generation revealed significant transcriptome dyregulation in pateints with severe COVID-19 that was largely different from SARS-CoV-2 negative patients in the ICU.
2022-04-08 | GSE178246 | GEO
Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is the reason for this ongoing pandemic infection diseases termed coronavirus disease 2019 (COVID-19) that has emerged since early December 2019 in Wuhan City, Hubei Province, China. In this century, it is the worst threat to international health and the economy. After 4 months of COVID-19 outbreak, there is no certain and approved medicine against it. In this public health emergency, it makes sense to investigate the possible effects of old drugs and find drug repositioning that is efficient, economical, and riskless process. Old drugs that may be effective are from different pharmacological categories, antimalarials, anthelmintics, anti-protozoal, anti-HIVs, anti-influenza, anti-hepacivirus, antineoplastics, neutralizing antibodies, immunoglobulins, and interferons. In vitro, in vivo, or preliminary trials of these drugs in the treatment of COVID-19 have been encouraging, leading to new research projects and trials to find the best drug/s. In this review, we discuss the possible mechanisms of these drugs against COVID-19. Also, it should be mentioned that in this manuscript, we discuss preliminary rationales; however, clinical trial evidence is needed to prove them. COVID-19 therapy must be based on expert clinical experience and published literature and guidelines from major health organizations. Moreover, herein, we describe current evidence that may be changed in the future.
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