scholarly journals Structural Biology Illuminates Molecular Determinants of Broad Ebolavirus Neutralization by Human Antibodies for Pan-Ebolavirus Therapeutic Development

2022 ◽  
Vol 12 ◽  
Author(s):  
Charles D. Murin ◽  
Pavlo Gilchuk ◽  
James E. Crowe ◽  
Andrew B. Ward

Monoclonal antibodies (mAbs) have proven effective for the treatment of ebolavirus infection in humans, with two mAb-based drugs Inmazeb™ and Ebanga™ receiving FDA approval in 2020. While these drugs represent a major advance in the field of filoviral therapeutics, they are composed of antibodies with single-species specificity for Zaire ebolavirus. The Ebolavirus genus includes five additional species, two of which, Bundibugyo ebolavirus and Sudan ebolavirus, have caused severe disease and significant outbreaks in the past. There are several recently identified broadly neutralizing ebolavirus antibodies, including some in the clinical development pipeline, that have demonstrated broad protection in preclinical studies. In this review, we describe how structural biology has illuminated the molecular basis of broad ebolavirus neutralization, including details of common antigenic sites of vulnerability on the glycoprotein surface. We begin with a discussion outlining the history of monoclonal antibody therapeutics for ebolaviruses, with an emphasis on how structural biology has contributed to these efforts. Next, we highlight key structural studies that have advanced our understanding of ebolavirus glycoprotein structures and mechanisms of antibody-mediated neutralization. Finally, we offer examples of how structural biology has contributed to advances in anti-viral medicines and discuss what opportunities the future holds, including rationally designed next-generation therapeutics with increased potency, breadth, and specificity against ebolaviruses.

2020 ◽  
Vol 15 ◽  
Author(s):  
Maria Carla Di Paolo ◽  
Cristiano Pagnini ◽  
Maria Giovanna Graziani

: Inflammatory bowel diseases (IBDs) are chronic conditions characterized by unknown etiology and pathogenesis with deregulation of mucosal immunity. Among possible treatments, corticosteroids, already available from the 50’, are still the mainstay of treatment for moderate-severe disease. Nonetheless, the use of steroids is still largely empirical and solid evidence about therapeutic schemes are lacking. Moreover, due to the important side-effects and for the unsatisfactory impact on long-term natural history of disease, the steroid sparing has become an important therapeutic goal in IBD management. Besides conventional steroids, the so called “low bioavailability” steroids, which are steroids with high affinity for peripheral receptors and elevated hepatic first-pass metabolism, have demonstrated efficacy and more favorable safety profile. In the present review of the literature evidence of efficacy and safety of conventional and low bioavailability steroids in IBD patients are evaluated, and practical suggestions for a correct use in clinical practice are presented according to the current clinical guidelines.


2021 ◽  
pp. 1-3
Author(s):  
Setareh Alabaf ◽  
Karen O'Connell ◽  
Sithara Ramdas ◽  
David Beeson ◽  
Jacqueline Palace

Congenital Myasthenic Syndrome (CMS) are a rare group of genetic disorders of neuromuscular transmission. Some subtypes of CMS can be associated with respiratory and bulbar weakness and these patients may therefore be at high risk of developing a severe disease from COVID-19. We screened 73 patients with genetically confirmed CMS who were attending the UK national referral centre for evidence of previous Severe Acute Respiratory Syndrome Corona Virus 2 infection and their clinical outcome. Of 73 patients, seven had history of confirmed COVID-19. None of the infected patients developed a severe disease, and there were no signals that CMS alone carries a high risk of severe disease from COVID-19.


2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Javier Fernández-López ◽  
M. Teresa Telleria ◽  
Margarita Dueñas ◽  
Mara Laguna-Castro ◽  
Klaus Schliep ◽  
...  

AbstractThe use of different sources of evidence has been recommended in order to conduct species delimitation analyses to solve taxonomic issues. In this study, we use a maximum likelihood framework to combine morphological and molecular traits to study the case of Xylodon australis (Hymenochaetales, Basidiomycota) using the locate.yeti function from the phytools R package. Xylodon australis has been considered a single species distributed across Australia, New Zealand and Patagonia. Multi-locus phylogenetic analyses were conducted to unmask the actual diversity under X. australis as well as the kinship relations respect their relatives. To assess the taxonomic position of each clade, locate.yeti function was used to locate in a molecular phylogeny the X. australis type material for which no molecular data was available using morphological continuous traits. Two different species were distinguished under the X. australis name, one from Australia–New Zealand and other from Patagonia. In addition, a close relationship with Xylodon lenis, a species from the South East of Asia, was confirmed for the Patagonian clade. We discuss the implications of our results for the biogeographical history of this genus and we evaluate the potential of this method to be used with historical collections for which molecular data is not available.


Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1135
Author(s):  
Bhubanananda Sahu ◽  
Isha Chug ◽  
Hemant Khanna

The eye is at the forefront of developing therapies for genetic diseases. With the FDA approval of the first gene-therapy drug for a form of congenital blindness, numerous studies have been initiated to develop gene therapies for other forms of eye diseases. These examinations have revealed new information about the benefits as well as restrictions to using drug-delivery routes to the different parts of the eye. In this article, we will discuss a brief history of gene therapy and its importance to the eye and ocular delivery landscape that is currently being investigated, and provide insights into their advantages and disadvantages. Efficient delivery routes and vehicle are crucial for an effective, safe, and longer-lasting therapy.


2006 ◽  
Vol 55 (2) ◽  
pp. 154-160 ◽  
Author(s):  
Antonio Egidio Nardi

This article aims to describe important points in the history of panic disorder concept, as well as to highlight the importance of its diagnosis for clinical and research developments. Panic disorder has been described in several literary reports and folklore. One of the oldest examples lies in Greek mythology - the god Pan, responsible for the term panic. The first half of the 19th century witnessed the culmination of medical approach. During the second half of the 19th century came the psychological approach of anxiety. The 20th century associated panic disorder to hereditary, organic and psychological factors, dividing anxiety into simple and phobic anxious states. Therapeutic development was also observed in psychopharmacological and psychotherapeutic fields. Official classifications began to include panic disorder as a category since the third edition of the American Classification Manual (1980). Some biological theories dealing with etiology were widely discussed during the last decades of the 20th century. They were based on laboratory studies of physiological, cognitive and biochemical tests, as the false suffocation alarm theory and the fear network. Such theories were important in creating new diagnostic paradigms to modern psychiatry. That suggests the need to consider a wide range of historical variables to understand how particular features for panic disorder diagnosis have been developed and how treatment has emerged.


Author(s):  
Nasir Uddin Ahmed ◽  
Md Azizul Islam ◽  
Md Anwarul Kabir ◽  
Md Habibur Rahman ◽  
SM Anwar Sadat

Introduction: COVID-19 is a major threat to human beings. Clinical characterization, rapid identification of cases and isolation are vital for containments of rapidly spreading disease. The objectives of the study were to evaluate the clinico pathologic profile of Covid 19 positive Bangladeshi patients and also to see their clinical outcome within defined period. Methods: This cohort study on 201 Bangladeshi cases was done in Combined Military Hospital, a tertiary level hospital in Dhaka, Bangladesh from April 2020 to May 2020. Total 201 COVID-19 cases were enrolled after getting the result positive for RT-PCR. After collection, data were analysed to show the characteristics of Covid 19 and their outcome after treatment. Results: Among 201 cases, 180 (90%) were male and 21 (10%) were female. The most prevalent affected age groups were 71 (35.5%) patients in 26-35 years age, 54 (27%) in 16- 25 years, 49 (24.5%) in 35-45 years. Mean age is 32.2±2. Among the total cases, 146 (73%) have positive history of contact, 37 (18.5%) have no history of any contact, 8 (4%) denied any contact with COVID-19 patients. Regarding clinical presentations, 67 (33.5%) patients presented with only one symptoms, 125 (62.5%) had multiple symptoms and 9 (4.5%) cases were asymptomatic. 154 (77%) patients presented with fever. Other presentations were cough 71 (35.5%), headache 27 (13.5%), myalgia 25 (12.5%), sore throat 25 (12.5%), malaise 15 (7.5%), respiratory distress 11 (5.5%). Respiratory system was the dominant domain of clinical presentation. Leukopenia was presented by 12 patients and 12 had lymphopenia. 18 patients had mild thrombocytopenia. Pulse oxymetry showed oxygen saturation below 88% in 12 cases. After oxygen therapy 7 cases were improved and 5 cases were shifted to Corona ICU as their saturation fell below 70. These 5 patients are categorised as severe disease, rest 196 patients were mild in nature. Conclusion: COVID 19 affects male more than female. Common symptoms are fever, cough, headache, myalgia, sore throat, malaise, respiratory distress. Respiratory system is the dominant domain of clinical presentation. ICU support was needed in 2.5 % cases and death rate was 1% which was associated with comorbidity of CKD. J Bangladesh Coll Phys Surg 2020; 38(0): 37-42


2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S501-S501
Author(s):  
O Lior ◽  
I Sergeev ◽  
N Ruhimovich ◽  
M Openheim ◽  
F Benjaminov ◽  
...  

Abstract Background Current inflammatory bowel disease (IBD) therapies are highly effective. However, compliance with treatment is influenced by patients’ perception of benefits versus risks. Understanding these perceptions and their influence on patients’ treatment decision-making is crucial for achieving compliance, especially during Covid-19 pandemic. Aim: to assess patients’ perception of risks of IBD exacerbation and SARS-CoV-2 infection, and their influence on patients’ decisions regarding biologic and immunosuppressive treatments during Covid-19 pandemic in Israel. Methods A prospective internet-based survey among Meir Medical Center, IBD clinic patients. Results 116 patients have responded. Mean age 42 (18–84), 44 (38%) males, 75 (64%) Crohn’s disease, 38 (32%) ulcerative colitis, 34 (29%) with history of abdominal surgery, 47 (40%) were in remission and 9(7.5%) with severe disease. 18 (15%) patients were on Immunosuppressive and 76 (66%) on biologic treatments. Concerns of contracting SARS-CoV-2 infection: 56 (48%) patients considered their risk as equal to that of the general population whereas 53 (46%) considered it to be increased. 55% of the patients related the increase risk of COVID-19 infection to their IBD treatment, whereas 47% related it to having IBD. Patients treated with biologics were more concerned of becoming infected with SARS-CoV-2 then those who were not. There was also a significant association between depression and anxiety levels and the fear of becoming infected (r= 0.3 for depression and 0.4 for anxiety). Adherence to IBD treatment: Only 8 (7.5%) patients considered stopping their IBD treatment, and only 4 (3.7%) patients actually stopped their treatment. Patients with more severe disease were more inclined to stop their treatment compared to those with mild disease. Reasons for not stopping treatment were fear of disease exacerbation in 37 (32%) patients, and reassuring information received from medical providers, in 25 (21.5%) patients. When faced with a theoretical question of trading long-term remission versus risk of SARS-CoV-2infection, 34 (29%) patients were willing to accept a 10% infection risk for a 10-year remission Conclusion Significant portion of the patients with IBD believe that they are at increased risk of contracting SARS-CoV-2 infection, and more than half of them related the increase risk to their IBD treatment. However, despite their fear most patients felt safe enough to continue their treatment. Patients with more severe disease and treated with biologics experienced higher levels of anxiety, depression and fear of COVID-19 infection. Identifying and addressing these fears early might increase patient’s adherence to treatment and prevent the hazardous effects of discontinuation of treatment.


mBio ◽  
2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Arturo Casadevall ◽  
Liise-anne Pirofski ◽  
Michael J. Joyner

ABSTRACT Antibody therapies such as convalescent plasma and monoclonal antibodies have emerged as major potential therapeutics for coronavirus disease 2019 (COVID-19). Immunoglobulins differ from conventional antimicrobial agents in that they mediate direct and indirect antimicrobial effects that work in concert with other components of the immune system. The field of infectious diseases pioneered antibody therapies in the first half of the 20th century but largely abandoned them with the arrival of conventional antimicrobial therapy. Consequently, much of the knowledge gained from the historical development and use of immunoglobulins such as serum and convalescent antibody therapies was forgotten; principles and practice governing their use were not taught to new generations of medical practitioners, and further development of this modality stalled. This became apparent during the COVID-19 pandemic in the spring of 2020 when convalescent plasma was initially deployed as salvage therapy in patients with severe disease. In retrospect, this was a stage of disease when it was less likely to be effective. Lessons of the past tell us that antibody therapy is most likely to be effective when used early in respiratory diseases. This article puts forth three principles of antibody therapy, namely, specificity, temporal, and quantitative principles, connoting that antibody efficacy requires the administration of specific antibody, given early in course of disease in sufficient amount. These principles are traced to the history of serum therapy for infectious diseases. The application of the specificity, temporal, and quantitative principles to COVID-19 is discussed in the context of current use of antibody therapy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).


Author(s):  
Erinna F. Lee ◽  
W. Douglas Fairlie

The discovery of a new class of small molecule compounds that target the BCL-2 family of anti-apoptotic proteins is one of the great success stories of basic science leading to translational outcomes in the last 30 years. The eponymous BCL-2 protein was identified over 30 years ago due to its association with cancer. However, it was the unveiling of the biochemistry and structural biology behind it and its close relatives’ mechanism(s)-of-action that provided the inspiration for what are now known as ‘BH3-mimetics’, the first clinically approved drugs designed to specifically inhibit protein–protein interactions. Herein, we chart the history of how these drugs were discovered, their evolution and application in cancer treatment.


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