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.
{"title":"Developing Small-Molecule Inhibitors of Protein-Protein Interactions Involved in Viral Entry as Potential Antivirals for COVID-19","authors":"P. Buchwald","doi":"10.3389/fddsv.2022.898035","DOIUrl":"https://doi.org/10.3389/fddsv.2022.898035","url":null,"abstract":"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.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46304005","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 : 2022-04-13DOI: 10.3389/fddsv.2022.892057
M. Reboud-Ravaux, C. El Amri
The global spread of severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) variants is alarming. In addition to vaccines, effective antiviral agents are urgently needed to combat corona virus disease 2019 (COVID-19). In this review, we will give insights on several canonical approaches using current medicinal chemistry. They target host (TMPRSS2, cathepsins B/L, furin) and viral (3CLpro and PLPro) proteases involved in virus cell entry and virus production, respectively. Innovative mechanisms of drug action are now explored whereby the drug triggers a cellular event that reduces the level of disease-implicated protein or RNA. The potential therapeutic power of induced degradations of viral proteins by PROTACs and of RNA by RIBOTACs for the treatment of COVID-19 will be discussed. Degraders of host cell RNA-binding proteins (RNA-PROTACs) may also constitute a therapeutical opportunity. First applicated to oncology, these novel technologies may be of a particular interest to obtain therapeutics susceptible to act on mutated viruses.
{"title":"COVID-19 Therapies: Protease Inhibitions and Novel Degrader Strategies","authors":"M. Reboud-Ravaux, C. El Amri","doi":"10.3389/fddsv.2022.892057","DOIUrl":"https://doi.org/10.3389/fddsv.2022.892057","url":null,"abstract":"The global spread of severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) variants is alarming. In addition to vaccines, effective antiviral agents are urgently needed to combat corona virus disease 2019 (COVID-19). In this review, we will give insights on several canonical approaches using current medicinal chemistry. They target host (TMPRSS2, cathepsins B/L, furin) and viral (3CLpro and PLPro) proteases involved in virus cell entry and virus production, respectively. Innovative mechanisms of drug action are now explored whereby the drug triggers a cellular event that reduces the level of disease-implicated protein or RNA. The potential therapeutic power of induced degradations of viral proteins by PROTACs and of RNA by RIBOTACs for the treatment of COVID-19 will be discussed. Degraders of host cell RNA-binding proteins (RNA-PROTACs) may also constitute a therapeutical opportunity. First applicated to oncology, these novel technologies may be of a particular interest to obtain therapeutics susceptible to act on mutated viruses.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46891040","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 : 2022-04-08DOI: 10.3389/fddsv.2022.892975
Evan F. Haney, R. Hancock
Antibiotic failure can be defined as any clinical situation where treatment with antibiotics fails to cure the patient and remove the infection. Genetically-determined antibiotic resistance certainly contributes to antibiotic failure in the clinic, but this is not the only reason why antibiotics fail and it is likely not the most common cause of antibiotic failure. In this perspective article, we outline several widespread examples of situations where antibiotic treatment fails, even in the absence of formal resistance, including biofilm associated-infections (65% of all infections) as well as infections in sepsis (19.7% of all deaths) and immune compromised individuals. We then discuss various strategies that are being employed to address the issue of antibiotic failure and emphasize that antibiotic failure should be given increased awareness and resources to address this underappreciated but critical issue.
{"title":"Addressing Antibiotic Failure—Beyond Genetically Encoded Antimicrobial Resistance","authors":"Evan F. Haney, R. Hancock","doi":"10.3389/fddsv.2022.892975","DOIUrl":"https://doi.org/10.3389/fddsv.2022.892975","url":null,"abstract":"Antibiotic failure can be defined as any clinical situation where treatment with antibiotics fails to cure the patient and remove the infection. Genetically-determined antibiotic resistance certainly contributes to antibiotic failure in the clinic, but this is not the only reason why antibiotics fail and it is likely not the most common cause of antibiotic failure. In this perspective article, we outline several widespread examples of situations where antibiotic treatment fails, even in the absence of formal resistance, including biofilm associated-infections (65% of all infections) as well as infections in sepsis (19.7% of all deaths) and immune compromised individuals. We then discuss various strategies that are being employed to address the issue of antibiotic failure and emphasize that antibiotic failure should be given increased awareness and resources to address this underappreciated but critical issue.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49254189","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 : 2022-03-30DOI: 10.3389/fddsv.2022.837587
A. C. Puhl, T. Lane, Fabio Urbina, S. Ekins
While we currently have multiple highly effective vaccines approved for use against SARS-CoV-2 in the USA and other countries, there are far fewer small molecule antivirals approved to date. The emergence of the latest SARS-CoV-2 variant, Omicron which is heavily mutated in the spike protein, is also raising concerns about the effectiveness of these current vaccines and increasing the call for more therapeutic options. At the time of writing only remdesivir is approved by the FDA while molnupiravir (already approved in the United Kingdom) and Paxlovid (PF-07321332) have emergency use authorizations from the FDA. Repurposed molecules, such as dexamethasone and baricitinib, have been authorized for emergency use in some countries and are used in combination with remdesivir. After 2 years we are only now starting to see the progression of further molecules through animal models to assess their efficacy before clinical trials. As datasets accumulate from both in vitro and in vivo animal efficacy models, this may allow us to understand the physicochemical properties necessary for antiviral activity and enable the search for additional antivirals. We now summarize 25 small molecule drugs that are either approved, in the process of approval or in the pipeline for COVID which have both in vitro and in vivo data. We demonstrate that these drugs are structurally diverse and cover a wide chemistry space. This information may aid our understanding of what it takes to be a promising treatment for COVID-19 and propose how to discover antivirals faster and more efficiently for the next pandemic. Graphical Abstract
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