scholarly journals Omicron favors neuropilin1 binding over ACE2: Increased infectivity and available drugs

Author(s):  
Piyush Baindara ◽  
Dinata Roy ◽  
Santi M. Mandal

Abstract COVID-19 pandemic is continue with thousands of new cases every day around the world, even then different vaccines have been developed and proven efficacious against SARS-CoV-2. Several know antivirals drugs have been repurposed or tested against SARS-CoV-2 but we still don’t have an effective therapeutic strategy to control this viral infection. Moreover, in the race of finding out an efficient antiviral, excess uses of antiviral drugs developed a selective pressure on the virus that results in the high frequency of mutations and the possible emergence of antiviral drug resistance against SARS-CoV-2. Omicron is a recently emerged, highly mutated variant of SARS-CoV-2, reported for high infectivity. In the present study, we performed molecular docking analysis between available potential antiviral drugs (remdesivir, nirmatrelvir, molnupiravir, EIDD-1931, GS-441524, and favipiravir) and omicron S protein including S protein/ACE2 complex. Our results suggest high infectivity of omicron, however, the known antiviral drugs were found efficacious against omicron variant. Further, to investigate the high infectivity of omicron, we performed a docking experiment between omicron S protein and neuropilin1 (NRP1). Surprisingly, results suggest high affinities with NRP1 than ACE2. Overall, results suggest that omicron favors NRP1 binding over ACE2, the possible reason behind improved infectivity of omicron variant.

Viruses ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 106
Author(s):  
Camilla Isgrò ◽  
Anna Maria Sardanelli ◽  
Luigi Leonardo Palese

In 2019 an outbreak occurred which resulted in a global pandemic. The causative agent has been identified in a virus belonging to the Coronaviridae family, similar to the agent of SARS, referred to as SARS-CoV-2. This epidemic spread rapidly globally with high morbidity and mortality. Although vaccine development is at a very advanced stage, there are currently no truly effective antiviral drugs to treat SARS-CoV-2 infection. In this study we present systematic and integrative antiviral drug repurposing effort aimed at identifying, among the drugs already authorized for clinical use, some active inhibitors of the SARS-CoV-2 main protease. The most important result of this analysis is the demonstration that ethacrynic acid, a powerful diuretic, is revealed to be an effective inhibitor of SARS-CoV-2 main protease. Even with all the necessary cautions, given the particular nature of this drug, these data can be the starting point for the development of an effective therapeutic strategy against SARS-CoV-2.


Coronaviruses ◽  
2020 ◽  
Vol 01 ◽  
Author(s):  
Manish Kumar ◽  
Chandra Prakash Jain

Background: An outbreak of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection or COVID 19, causing serious threats to all around the world. Until an effective and safe vaccine for novel coronavirus is developed by scientists, current drug therapy should by optimize for the control and treatment of COVID 19. Objective: In this manuscript, we are presenting a perspective on possible benefits of reformulating antiviral drug dosage form with nanoemulsion system against novel coronavirus infection. Methods: Literature review has been done on COVID 19, treatment strategies, novel drug delivery systems and role of pulmonary surfactant on lungs protection. Results: Nanoemulsion system and its components have certain biophysical properties which could increase the efficacy of drug therapy. Antiviral drugs, delivered through a nanoemulsion system containing P-gp inhibitor (surfactant and cosolvent), can inhibit the cellular resistance to drugs and would potentiate the antiviral action of drugs. Pulmonary surfactant (PS) assisted antiviral drug delivery by nanoemulsion system could be another effective approach for the treatment of COVID 19. Use of functional excipients like pulmonary surfactant (PS) and surfactant proteins (SPs), in the formulation of the antiviral drug-loaded nanoemulsion system can improve the treatment of coronavirus infection. Conclusion: In our opinion for synergizing antiviral action, lipid and protein portion of PS and their commercial analogs should be explored by pharmaceutical scientists to use them as a functional excipient in the formulation of antiviral drugloaded nanoemulsion system.


Antibiotics ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 795
Author(s):  
Leticia Matilla-Cuenca ◽  
Alejandro Toledo-Arana ◽  
Jaione Valle

The choice of an effective therapeutic strategy in the treatment of biofilm-related infections is a significant issue. Amyloids, which have been historically related to human diseases, are now considered to be prevailing structural components of the biofilm matrix in a wide range of bacteria. This assumption creates the potential for an exciting research area, in which functional amyloids are considered to be attractive targets for drug development to dissemble biofilm structures. The present review describes the best-characterized bacterial functional amyloids and focuses on anti-biofilm agents that target intrinsic and facultative amyloids. This study provides a better understanding of the different modes of actions of the anti-amyloid molecules to inhibit biofilm formation. This information can be further exploited to improve the therapeutic strategies to combat biofilm-related infections.


2021 ◽  
Author(s):  
Jenna C. Carpenter ◽  
Gabriele Lignani

AbstractEpilepsy is a complex neurological disorder for which there are a large number of monogenic subtypes. Monogenic epilepsies are often severe and disabling, featuring drug-resistant seizures and significant developmental comorbidities. These disorders are potentially amenable to a precision medicine approach, of which genome editing using CRISPR/Cas represents the holy grail. Here we consider mutations in some of the most ‘common’ rare epilepsy genes and discuss the different CRISPR/Cas approaches that could be taken to cure these disorders. We consider scenarios where CRISPR-mediated gene modulation could serve as an effective therapeutic strategy and discuss whether a single gene corrective approach could hold therapeutic potential in the context of homeostatic compensation in the developing, highly dynamic brain. Despite an incomplete understanding of the mechanisms of the genetic epilepsies and current limitations of gene editing tools, CRISPR-mediated approaches have game-changing potential in the treatment of genetic epilepsy over the next decade.


2018 ◽  
Vol 24 (24) ◽  
pp. 6483-6494 ◽  
Author(s):  
Matthew Dankner ◽  
Mathieu Lajoie ◽  
Dan Moldoveanu ◽  
Tan-Trieu Nguyen ◽  
Paul Savage ◽  
...  

2021 ◽  
Author(s):  
Jiale Shi ◽  
Yuejun Shi ◽  
Ruixue Xiu ◽  
Gang Wang ◽  
Rui Liang ◽  
...  

The receptor binding domain (RBD) of the coronavirus spike protein (S) has been verified to be the main target for potent neutralizing antibodies (nAbs) in most coronaviruses, and the N-terminal domain (NTD) of some betacoronaviruses has also been indicated to induce nAbs. For alphacoronavirus HCoV-229E, its RBD has been shown to have neutralizing epitopes, and these epitopes could change over time. However, whether neutralizing epitopes exist on the NTD and whether these epitopes change like those of the RBD are still unknown. Here, we verified that neutralizing epitopes exist on the NTD of HCoV-229E. Furthermore, we characterized an NTD targeting nAb 5H10, which could neutralize both pseudotyped and authentic HCoV-229E VR740 in vitro. Epitope mapping indicated that 5H10 targeted motif E1 (147-167 aa) and identified F159 as critical for 5H10 binding. More importantly, our results revealed that motif E1 was highly conserved among clinical isolates except for F159. Further data proved that mutations at position 159 gradually appeared over time and could completely abolish the neutralizing ability of 5H10, supporting the notion that position 159 may be under selective pressure during the human epidemic. In addition, we also found that contemporary clinical serum has a stronger binding capacity for the NTD of contemporary strains than historic strains, proving that the epitope on the NTD could change over time. In summary, these findings define a novel neutralizing epitope on the NTD of HCoV-229E S and provide a theoretical basis for the design of vaccines against HCoV-229E or related coronaviruses. Importance Characterization of the neutralizing epitope of the spike (S) protein, the major invasion protein of coronaviruses, can help us better understand the evolutionary characteristics of these viruses and promote vaccine development. To date, the neutralizing epitope distribution of alphacoronaviruses is not well known. Here, we identified a neutralizing antibody that targeted the N-terminal domain (NTD) of the alphacoronavirus HCoV-229E S protein. Epitope mapping revealed a novel epitope that was not previously discovered in HCoV-229E. Further studies identified an important residue, F159. Mutations that gradually appeared over time at this site abolished the neutralizing ability of 5H10, indicating that selective pressure occurred at this position in the spread of HCoV-229E. Furthermore, we found that the epitopes within the NTD also changed over time. Taken together, our findings defined a novel neutralizing epitope and highlighted the role of the NTD in the future prevention and control of HCoV-229E or related coronaviruses.


2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Soichiro Obata ◽  
Michi Kasai ◽  
Junko Kasai ◽  
Kazuo Seki ◽  
Zenjiro Sekikawa ◽  
...  

Although it is widely accepted that uterine artery embolization (UAE) is an effective therapeutic strategy for postpartum hemorrhage (PPH), no consensus has been reached regarding the efficacy of UAE in patients with PPH with disseminated intravascular coagulation (DIC). This single-center retrospective cohort study included patients treated with UAE using NBCA for PPH between 2010 and 2015. The patients were divided into DIC and non-DIC groups, according to the obstetrical DIC score and the overt DIC diagnostic criteria issued by the International Society of Thrombosis and Haemostasis (ISTH), and their clinical outcomes were compared. There were 28 patients treated with UAE using NBCA. Complete hemostasis was achieved by UAE in 19 of 28 patients. In eight of nine patients with unsuccessful hemostasis, surgical hemostatic interventions were performed after UAE, and hemostasis was achieved in seven patients. UAE using NBCA showed no significant intergroup differences in complete hemostasis according to the presence or absence of DIC based on obstetrical DIC score (70% versus 62.5%, P=1.000) or ISTH DIC score (54.5% versus 76.5%, P=0.409). UAE using NBCA may be a useful first-choice treatment for PPH with DIC.


2018 ◽  
Vol 46 (04) ◽  
pp. 707-737 ◽  
Author(s):  
Zefeng Zhao ◽  
Xirui He ◽  
Cuixia Ma ◽  
Shaoping Wu ◽  
Ye Cuan ◽  
...  

Traditional Chinese medicine (TCM) has a long history and been widely used in prevention and treatment of epilepsy in China. This paper is intended to review the advances in the active anticonvulsant compounds isolated from herbs in the prescription of TCM in the treatment of epilepsy. These compounds were introduced with the details including classification, CAS number specific structure and druggability data. Meanwhile, much of the research in these compounds in the last two decades has shown that they exhibited favorable pharmacological properties in treatment of epilepsy both in in vivo and in vitro models. In addition, in this present review, the evaluation of the effects of the anticonvulsant classical TCM prescriptions is discussed. According to these rewarding pharmacological effects and chemical substances, the prescription of TCM herbs could be an effective therapeutic strategy for epilepsy patients, and also could be a promising source for the development of new drugs.


2020 ◽  
Vol 319 (6) ◽  
pp. F1105-F1116
Author(s):  
Mingzhu Jiang ◽  
Mi Bai ◽  
Juan Lei ◽  
Yifan Xie ◽  
Shuang Xu ◽  
...  

Acute kidney injury (AKI) has been widely recognized as an important risk factor for the occurrence and development of chronic kidney disease (CKD). Even milder AKI has adverse consequences and could progress to renal fibrosis, which is the ultimate common pathway for various terminal kidney diseases. Thus, it is urgent to develop a strategy to hinder the transition from AKI to CKD. Some mechanisms of the AKI-to-CKD transition have been revealed, such as nephron loss, cell cycle arrest, persistent inflammation, endothelial injury with vascular rarefaction, and epigenetic changes. Previous studies have elucidated the pivotal role of mitochondria in acute injuries and demonstrated that the fitness of this organelle is a major determinant in both the pathogenesis and recovery of organ function. Recent research has suggested that damage to mitochondrial function in early AKI is a crucial factor leading to tubular injury and persistent renal insufficiency. Dysregulation of mitochondrial homeostasis, alterations in bioenergetics, and organelle stress cross talk contribute to the AKI-to-CKD transition. In this review, we focus on the pathophysiology of mitochondria in renal recovery after AKI and progression to CKD, confirming that targeting mitochondria represents a potentially effective therapeutic strategy for the progression of AKI to CKD.


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