Pub Date : 2022-08-24DOI: 10.3389/fddsv.2022.983030
Yuhai Zhao, V. Jaber, W. Lukiw
mRNA-mediated gene expression appears to be signi cantly in AD and CNS, our understanding of con fi guration and composition of circRNA is these ssRNAs are highly can in pathophysiological for extended periods, and therapeutically can be designed and synthesized to carry multiple ssRNA-mediated regulatory signals. Based on these and other very recent fi ndings this Opinion ” paper will: 1) address our current understanding of the emerging role of circRNAs in neurodegeneration with special reference to AD; and 2) discuss the intriguing possibility of using synthetic circRNAs containing multiple inserted miRNA, (AM; antagomir), anti-mRNA and/or other sequences in tandem combination with a personalized as an innovative for the and
{"title":"Current advances in our understanding of circular RNA (circRNA) in Alzheimer’s disease (AD); the potential utilization of synthetic circRNAs as a therapeutic strategy in the clinical management of AD","authors":"Yuhai Zhao, V. Jaber, W. Lukiw","doi":"10.3389/fddsv.2022.983030","DOIUrl":"https://doi.org/10.3389/fddsv.2022.983030","url":null,"abstract":"mRNA-mediated gene expression appears to be signi cantly in AD and CNS, our understanding of con fi guration and composition of circRNA is these ssRNAs are highly can in pathophysiological for extended periods, and therapeutically can be designed and synthesized to carry multiple ssRNA-mediated regulatory signals. Based on these and other very recent fi ndings this Opinion ” paper will: 1) address our current understanding of the emerging role of circRNAs in neurodegeneration with special reference to AD; and 2) discuss the intriguing possibility of using synthetic circRNAs containing multiple inserted miRNA, (AM; antagomir), anti-mRNA and/or other sequences in tandem combination with a personalized as an innovative for the and","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47640914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-08-11DOI: 10.3389/fddsv.2022.948407
Chun Chou, M. Chin
Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical syndrome characterized by signs and symptoms of HF in the presence of a normal left ventricular systolic function. Over the past decade, HFpEF has become increasingly prevalent, accounting for greater than 50% of all clinical HF presentations. HFpEF is a complex disease with heterogeneous clinical presentations and multiple non-cardiac comorbidities, which frequently co-exist and contribute to its pathophysiology. To date, only a handful of therapies have been proven to improve, albeit marginally, the outcomes in HFpEF. The development of effective therapeutic agents is in part hampered by the lack of animal models that adequately recapitulate human HFpEF. Although numerous pre-clinical models developed over the years have been labeled as “HFpEF” specific, there has not been a consensus on the appropriate standards for pre-clinical HFpEF models. Thus, the extent to which they truly mirror human HFpEF cannot be systematically validated. Recently, a new algorithm (H2FPEF) was developed to standardize the clinical diagnosis of HFpEF. In this review, with the aid of the clinical H2FPEF scoring system, we evaluate the clinical applicability and translational values of various murine models of HFpEF.
{"title":"Modeling heart failure with preserved ejection fraction in rodents: Where do we stand?","authors":"Chun Chou, M. Chin","doi":"10.3389/fddsv.2022.948407","DOIUrl":"https://doi.org/10.3389/fddsv.2022.948407","url":null,"abstract":"Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical syndrome characterized by signs and symptoms of HF in the presence of a normal left ventricular systolic function. Over the past decade, HFpEF has become increasingly prevalent, accounting for greater than 50% of all clinical HF presentations. HFpEF is a complex disease with heterogeneous clinical presentations and multiple non-cardiac comorbidities, which frequently co-exist and contribute to its pathophysiology. To date, only a handful of therapies have been proven to improve, albeit marginally, the outcomes in HFpEF. The development of effective therapeutic agents is in part hampered by the lack of animal models that adequately recapitulate human HFpEF. Although numerous pre-clinical models developed over the years have been labeled as “HFpEF” specific, there has not been a consensus on the appropriate standards for pre-clinical HFpEF models. Thus, the extent to which they truly mirror human HFpEF cannot be systematically validated. Recently, a new algorithm (H2FPEF) was developed to standardize the clinical diagnosis of HFpEF. In this review, with the aid of the clinical H2FPEF scoring system, we evaluate the clinical applicability and translational values of various murine models of HFpEF.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44510927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-08-10DOI: 10.3389/fddsv.2022.953988
Maycon Marção, S. Müller, Pedro Luiz P. Xavier, T. Malta
Stemness is a phenotype associated with cancer initiation and progression, malignancy, and therapeutic resistance, exhibiting particular molecular signatures. Targeting stemness has been proposed as a promising strategy against breast cancer stem cells that can play a key role in breast cancer progression, metastasis, and multiple drug resistance. Here, using a previously published one-class logistic regression machine learning algorithm (OCLR) built on pluripotent stem cells to predict stemness in human cancer samples, we provide the stemness index (mRNAsi) of different canine non-tumor and mammary cancer cells. Then, we confirmed that inhibition of BET proteins by (+)-JQ1 reduces stemness in a high mRNAsi canine cancer cell. Furthermore, using public data, we observed that (+)-JQ1 can also decrease stemness in human triple-negative breast cancer cells. Our work suggests that mRNAsi can be used to estimate stemness in different species and confirm epigenetic modulation by BET inhibition as a promising strategy for modulating the stemness phenotype in canine and human mammary cancer cells.
{"title":"Stemness inhibition by (+)-JQ1 in canine and human mammary cancer cells revealed by machine learning","authors":"Maycon Marção, S. Müller, Pedro Luiz P. Xavier, T. Malta","doi":"10.3389/fddsv.2022.953988","DOIUrl":"https://doi.org/10.3389/fddsv.2022.953988","url":null,"abstract":"Stemness is a phenotype associated with cancer initiation and progression, malignancy, and therapeutic resistance, exhibiting particular molecular signatures. Targeting stemness has been proposed as a promising strategy against breast cancer stem cells that can play a key role in breast cancer progression, metastasis, and multiple drug resistance. Here, using a previously published one-class logistic regression machine learning algorithm (OCLR) built on pluripotent stem cells to predict stemness in human cancer samples, we provide the stemness index (mRNAsi) of different canine non-tumor and mammary cancer cells. Then, we confirmed that inhibition of BET proteins by (+)-JQ1 reduces stemness in a high mRNAsi canine cancer cell. Furthermore, using public data, we observed that (+)-JQ1 can also decrease stemness in human triple-negative breast cancer cells. Our work suggests that mRNAsi can be used to estimate stemness in different species and confirm epigenetic modulation by BET inhibition as a promising strategy for modulating the stemness phenotype in canine and human mammary cancer cells.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44335983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-07-18DOI: 10.3389/fddsv.2022.927164
Guillermo Valenzuela-Nieto, Zaray Miranda-Chacón, Constanza Salinas-Rebolledo, Ronald Jara, Alexei Cuevas, Anne D. Berking, A. Rojas-Fernandez
The COVID-19 pandemic has driven biotechnological developments to provide new and more effective tools for prophylaxis, diagnosis, and therapy. Historically, monoclonal antibodies have been valuable tools; however, the pandemic has shown some weaknesses, such as production limitations at a global scale. An alternative to conventional monoclonal antibodies are nanobodies, recombinant fragments of the variable region of single-domain antibodies derived mainly from the Camelidae family. Nanobodies have multiple characteristic benefits: they are small (15 KDa) and have remarkable refolding capability and unlimited possibilities for modifications due to their recombinant nature. Here, we review the application of nanobodies in diagnosis and treatment of SARS-CoV-2 infection.
{"title":"Nanobodies: COVID-19 and Future Perspectives","authors":"Guillermo Valenzuela-Nieto, Zaray Miranda-Chacón, Constanza Salinas-Rebolledo, Ronald Jara, Alexei Cuevas, Anne D. Berking, A. Rojas-Fernandez","doi":"10.3389/fddsv.2022.927164","DOIUrl":"https://doi.org/10.3389/fddsv.2022.927164","url":null,"abstract":"The COVID-19 pandemic has driven biotechnological developments to provide new and more effective tools for prophylaxis, diagnosis, and therapy. Historically, monoclonal antibodies have been valuable tools; however, the pandemic has shown some weaknesses, such as production limitations at a global scale. An alternative to conventional monoclonal antibodies are nanobodies, recombinant fragments of the variable region of single-domain antibodies derived mainly from the Camelidae family. Nanobodies have multiple characteristic benefits: they are small (15 KDa) and have remarkable refolding capability and unlimited possibilities for modifications due to their recombinant nature. Here, we review the application of nanobodies in diagnosis and treatment of SARS-CoV-2 infection.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44316335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-07-15DOI: 10.3389/fddsv.2022.910124
H. Kaplan, Kai Wang, Kimberly M. Reeves, J. Scanlan, Christopher C. Nunn, D. Kieper, Joshua L. Mark, Inyoul Y. Lee, Rachel Liu, R. Jin, Michael J. Bolton, J. Goldman
Background: Safe, effective, and inexpensive treatment for COVID-19 is an urgent unmet medical need. Zinc and resveratrol have been reported to have antiviral activity, and resveratrol may increase zinc activity at the site of replication by increasing intracellular zinc concentrations.Methods: A 1:1 randomized, placebo-controlled trial of zinc 150 mg plus resveratrol 4 g daily for 5 days versus placebos in outpatients with SARS-CoV-2 was carried out from 9/21/2020–1/22/2021 in Seattle, Washington. Viral shedding was followed with patient self-collected nasal and saliva samples by measuring qRT-PCR for SARS-CoV-2 N gene days 1–7, 10, and 14. Patients filled out a web-based questionnaire on days 1–14 to report symptoms, vital signs and adherence to the study intervention. The study was posted as Clinical Trials.gov NCT04542993 on 9 September 2020.Results: A total of 30 participants (14 treatment; 16 placebos) had ≥1 day of the protocol treatment and were evaluable for the primary or secondary outcome. There was no difference in viral shedding between groups, nor in the resolution of symptoms. There was a trend toward a more rapid decrease in symptoms in the treatment group, though this was not statistically significant in the GLM model. Viral shedding was similar between patient self-collected mid-turbinate nasal swabs and expectorated saliva samples with a good correlation.Conclusion: SARS-CoV-2 shedding and COVID-19 symptoms were not statistically significantly decreased by treatment. Viral shedding correlates well between patient-obtained home nasal swabs and saliva sampling.
{"title":"Reszinate—A Phase 1/2 Randomized Clinical Trial of Zinc and Resveratrol Utilizing Home Patient-Obtained Nasal and Saliva Viral Sampling","authors":"H. Kaplan, Kai Wang, Kimberly M. Reeves, J. Scanlan, Christopher C. Nunn, D. Kieper, Joshua L. Mark, Inyoul Y. Lee, Rachel Liu, R. Jin, Michael J. Bolton, J. Goldman","doi":"10.3389/fddsv.2022.910124","DOIUrl":"https://doi.org/10.3389/fddsv.2022.910124","url":null,"abstract":"Background: Safe, effective, and inexpensive treatment for COVID-19 is an urgent unmet medical need. Zinc and resveratrol have been reported to have antiviral activity, and resveratrol may increase zinc activity at the site of replication by increasing intracellular zinc concentrations.Methods: A 1:1 randomized, placebo-controlled trial of zinc 150 mg plus resveratrol 4 g daily for 5 days versus placebos in outpatients with SARS-CoV-2 was carried out from 9/21/2020–1/22/2021 in Seattle, Washington. Viral shedding was followed with patient self-collected nasal and saliva samples by measuring qRT-PCR for SARS-CoV-2 N gene days 1–7, 10, and 14. Patients filled out a web-based questionnaire on days 1–14 to report symptoms, vital signs and adherence to the study intervention. The study was posted as Clinical Trials.gov NCT04542993 on 9 September 2020.Results: A total of 30 participants (14 treatment; 16 placebos) had ≥1 day of the protocol treatment and were evaluable for the primary or secondary outcome. There was no difference in viral shedding between groups, nor in the resolution of symptoms. There was a trend toward a more rapid decrease in symptoms in the treatment group, though this was not statistically significant in the GLM model. Viral shedding was similar between patient self-collected mid-turbinate nasal swabs and expectorated saliva samples with a good correlation.Conclusion: SARS-CoV-2 shedding and COVID-19 symptoms were not statistically significantly decreased by treatment. Viral shedding correlates well between patient-obtained home nasal swabs and saliva sampling.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42536398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-05-26DOI: 10.3389/fddsv.2022.898654
E. Gold, A. Edwards
Among the lessons learned from the COVID-19 pandemic is the need to develop antiviral drugs poised to treat the next pandemic. Unfortunately, traditional drug development economic models, centered principally on patents, are ineffective to induce private sector investment due to unpredictable timing and cause of the next pandemic. As a result, illustrated by the COVID-19 pandemic, it is the public and philanthropic sectors sectors that overwhelmingly fund the development of innovative vaccines and therapies. To meet the need for proactive antiviral medicines in advance of the next pandemic, new models of drug development are needed. Open science partnerships (OSPs) show promise in this regard. Rather than rely principally on patents and private investment, OSPs combine a variety of academic, philanthropic, governmental, and private sector incentives to share knowledge and develop and test antiviral drugs. Private sector investments are, within an OSP, not only leveraged against investments by other actors, but predicated on gaining regulatory data exclusivity, a known and secure form of commercial advantage. Building on domestic expertise in OSPs, Canadian leaders created the Viral Interruption Medicines Initiative, a not-for-profit OSP, to develop pandemic ready-antivirals and address other areas of market failure.
{"title":"Overcoming Market Failures in Pandemic Drug Discovery Through Open Science: A Canadian Solution","authors":"E. Gold, A. Edwards","doi":"10.3389/fddsv.2022.898654","DOIUrl":"https://doi.org/10.3389/fddsv.2022.898654","url":null,"abstract":"Among the lessons learned from the COVID-19 pandemic is the need to develop antiviral drugs poised to treat the next pandemic. Unfortunately, traditional drug development economic models, centered principally on patents, are ineffective to induce private sector investment due to unpredictable timing and cause of the next pandemic. As a result, illustrated by the COVID-19 pandemic, it is the public and philanthropic sectors sectors that overwhelmingly fund the development of innovative vaccines and therapies. To meet the need for proactive antiviral medicines in advance of the next pandemic, new models of drug development are needed. Open science partnerships (OSPs) show promise in this regard. Rather than rely principally on patents and private investment, OSPs combine a variety of academic, philanthropic, governmental, and private sector incentives to share knowledge and develop and test antiviral drugs. Private sector investments are, within an OSP, not only leveraged against investments by other actors, but predicated on gaining regulatory data exclusivity, a known and secure form of commercial advantage. Building on domestic expertise in OSPs, Canadian leaders created the Viral Interruption Medicines Initiative, a not-for-profit OSP, to develop pandemic ready-antivirals and address other areas of market failure.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45960554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-05-10DOI: 10.3389/fddsv.2022.899239
B. Villoutreix, I. Badiola, A. Khatib
Furin is involved in the endoproteolytic processing of various protein precursors implicated in many diseases such as diabetes, obesity, atherosclerosis, cancer, Alzheimer’s disease and viral infection including COVID-19. Recently, cell entry of SARS-CoV-2 was found to require sequential cleavage of the viral spike glycoprotein (S protein) at the S1/S2 and the S2ʹ cleavage sites. The S1/S2 site (PRRAR) can be cleaved by the proprotein convertase furin that facilitates membrane fusion and viral spread. Here we summarized the recent findings on furin and S protein structures, the role of S protein cleavage by furin during SARS-CoV-2 infection. We analyzed 12 diverse representative inhibitors of furin using a chemoinformatic approach starting from a list of 628 compounds downloaded from the ChEMBL database. Among those, only 76 survived a soft rule of five filtering step. Structural alerts are present on most of these molecules while some compounds are also predicted to act on toxicity targets. No clinical trials are presently listed at the ClinicalTrials.gov website regarding small molecule inhibitors of furin.
{"title":"Furin and COVID-19: Structure, Function and Chemoinformatic Analysis of Representative Active Site Inhibitors","authors":"B. Villoutreix, I. Badiola, A. Khatib","doi":"10.3389/fddsv.2022.899239","DOIUrl":"https://doi.org/10.3389/fddsv.2022.899239","url":null,"abstract":"Furin is involved in the endoproteolytic processing of various protein precursors implicated in many diseases such as diabetes, obesity, atherosclerosis, cancer, Alzheimer’s disease and viral infection including COVID-19. Recently, cell entry of SARS-CoV-2 was found to require sequential cleavage of the viral spike glycoprotein (S protein) at the S1/S2 and the S2ʹ cleavage sites. The S1/S2 site (PRRAR) can be cleaved by the proprotein convertase furin that facilitates membrane fusion and viral spread. Here we summarized the recent findings on furin and S protein structures, the role of S protein cleavage by furin during SARS-CoV-2 infection. We analyzed 12 diverse representative inhibitors of furin using a chemoinformatic approach starting from a list of 628 compounds downloaded from the ChEMBL database. Among those, only 76 survived a soft rule of five filtering step. Structural alerts are present on most of these molecules while some compounds are also predicted to act on toxicity targets. No clinical trials are presently listed at the ClinicalTrials.gov website regarding small molecule inhibitors of furin.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48114310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-05-10DOI: 10.3389/fddsv.2022.899477
G. Moroy, P. Tufféry
Because of its scale and suddenness, the SARS-CoV-2 pandemic has created an unprecedented challenge in terms of drug development. Apart from being natural candidates for vaccine design, peptides are a class of compounds well suited to target protein-protein interactions, and peptide drug development benefits from the progress of in silico protocols that have emerged within the last decade. Here, we review the different strategies that have been considered for the development of peptide drugs against SARS-CoV-2. Thanks to progress in experimental structure determination, structural information has rapidly become available for most of the proteins encoded by the virus, easing in silico analyses to develop drugs or vaccines. The repurposing of antiviral/antibacterial peptide drugs has not been successful so far. The most promising results, but not the only ones, have been obtained targeting the interaction between SARS-CoV-2 spike protein and the Angiotensin-Converting Enzyme 2, which triggers cellular infection by the virus and its replication. Within months, structure-based peptide design has identified competing for picomolar candidates for the interaction, proving that the development of peptide drugs targeting protein-protein interactions is maturing. Although no drug specifically designed against SARS-CoV-2 has yet reached the market, lessons from peptide drug development against SARS-CoV-2 suggest that peptide development is now a plausible alternative to small compounds.
{"title":"Peptide-Based Strategies Against SARS-CoV-2 Attack: An Updated In Silico Perspective","authors":"G. Moroy, P. Tufféry","doi":"10.3389/fddsv.2022.899477","DOIUrl":"https://doi.org/10.3389/fddsv.2022.899477","url":null,"abstract":"Because of its scale and suddenness, the SARS-CoV-2 pandemic has created an unprecedented challenge in terms of drug development. Apart from being natural candidates for vaccine design, peptides are a class of compounds well suited to target protein-protein interactions, and peptide drug development benefits from the progress of in silico protocols that have emerged within the last decade. Here, we review the different strategies that have been considered for the development of peptide drugs against SARS-CoV-2. Thanks to progress in experimental structure determination, structural information has rapidly become available for most of the proteins encoded by the virus, easing in silico analyses to develop drugs or vaccines. The repurposing of antiviral/antibacterial peptide drugs has not been successful so far. The most promising results, but not the only ones, have been obtained targeting the interaction between SARS-CoV-2 spike protein and the Angiotensin-Converting Enzyme 2, which triggers cellular infection by the virus and its replication. Within months, structure-based peptide design has identified competing for picomolar candidates for the interaction, proving that the development of peptide drugs targeting protein-protein interactions is maturing. Although no drug specifically designed against SARS-CoV-2 has yet reached the market, lessons from peptide drug development against SARS-CoV-2 suggest that peptide development is now a plausible alternative to small compounds.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44522036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-05-02DOI: 10.3389/fddsv.2022.899587
Petr Nickl, Miles Joseph Raishbrook, L. Syding, R. Sedláček
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is a positive-sense-single stranded RNA virus and the cause of the coronavirus disease 2019 (COVID-19). The World Health Organisation has confirmed over 250 million cases with over 5.1 million deaths as a result of this pandemic since December 2019. A global outbreak of such intensity and perseverance is due to the novelty of SARS-CoV2 virus, meaning humans lack any pre-existing immunity to the virus. Humanised animal models, from rodents to primates, simulating SARS-CoV2 transmission, cell entry and immune defence in humans have already been crucial to boost understanding of its molecular mechanisms of infection, reveal at-risk populations, and study the pathophysiology in vivo. Focus is now turning towards using this knowledge to create effective vaccines and therapeutic agents, as well as optimise their safety for translatable use in humans. SARS-CoV2 possesses remarkable adaptability and rapid mutagenic capabilities thus exploiting innovative animal models will be pivotal to outmanoeuvre it during this pandemic. In this review, we summarise all generated SARS-CoV2-related animal models to date, evaluate their suitability for COVID-19 research, and address the current and future state of the importance of animal models in this field.
{"title":"Advances in Modelling COVID-19 in Animals","authors":"Petr Nickl, Miles Joseph Raishbrook, L. Syding, R. Sedláček","doi":"10.3389/fddsv.2022.899587","DOIUrl":"https://doi.org/10.3389/fddsv.2022.899587","url":null,"abstract":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is a positive-sense-single stranded RNA virus and the cause of the coronavirus disease 2019 (COVID-19). The World Health Organisation has confirmed over 250 million cases with over 5.1 million deaths as a result of this pandemic since December 2019. A global outbreak of such intensity and perseverance is due to the novelty of SARS-CoV2 virus, meaning humans lack any pre-existing immunity to the virus. Humanised animal models, from rodents to primates, simulating SARS-CoV2 transmission, cell entry and immune defence in humans have already been crucial to boost understanding of its molecular mechanisms of infection, reveal at-risk populations, and study the pathophysiology in vivo. Focus is now turning towards using this knowledge to create effective vaccines and therapeutic agents, as well as optimise their safety for translatable use in humans. SARS-CoV2 possesses remarkable adaptability and rapid mutagenic capabilities thus exploiting innovative animal models will be pivotal to outmanoeuvre it during this pandemic. In this review, we summarise all generated SARS-CoV2-related animal models to date, evaluate their suitability for COVID-19 research, and address the current and future state of the importance of animal models in this field.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41928730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-04-25DOI: 10.3389/fddsv.2022.898035
P. Buchwald
Blocking protein-protein interactions (PPIs) involved in the initiation of the cell attachment and entry of viruses is an important antiviral mechanism of action including for neutralizing antibodies. Doing it with small-molecule inhibitors (SMIs) is challenging, as it is for all other PPIs, and might require the exploration of chemical space beyond that of typical drug-like structures. However, it could lead to new antiviral agents suitable for oral administration and acting on alternative targets, considerations that are essential for the development of widely acceptable and broad-spectrum preventive or curative therapeutics. Fostemsavir, an antiretroviral that acts via blocking of the gp120–CD4 PPI, supports the feasibility of the concept. Here, a brief review of relevant drug design considerations is presented together with a summary of the progress made toward the identification of SMIs targeting the PPI between the SARS-CoV-2 spike protein and ACE2 that initiates the viral attachment and cellular entry of this coronavirus causing the COVID-19 pandemic. SMIs identified in various screening assays that were also confirmed to have antiviral activity in a live virus or pseudovirus assay with an IC50 < 30 µM so far include several organic dyes (methylene blue, Evans blue, Congo red, direct violet 1), verteporfin, DRI-C23041, and cannabigerolic and cannabidiolic acids. While specificity and activity profiles still need improvement, results so far already provide proof-of-principle evidence for the feasibility of SMIs targeting the SARS-CoV-2-S–hACE2 PPI. Methylene blue, which is approved for clinical use, is orally bioactive, and could act by multiple mechanisms of action, might have potential for repurposing for COVID-19 prevention and treatment.
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