Pub Date : 2023-06-15DOI: 10.3389/fddsv.2023.1190471
J. Chirawurah, Bridget Adikah, F. Ansah, E. Laryea-Akrong, Harry Danwonno, C. Morang’a, Daniel Dosoo, L. Amenga-Etego, G. Awandare, Y. Aniweh
The emergence of drug-resistant malaria parasites to artemisinin and its partner drugs highlights the need to increase the arsenal of new antimalarials with novel mechanisms of action. To help achieve this aim, this study tested the potency of three Malaria Box compounds (MMV006087, MMV085203, and MMV008956) against five laboratory strains and twenty clinical isolates of Plasmodium falciparum using optimized in vitro growth inhibitory assays. The results were compared to the response from four standard antimalarials-artesunate, chloroquine, mefloquine, and halofantrine. From the results, MMV006087 was the most potent compound with an average IC50 of 22.13 nM compared to MMV085203 (average IC50 of 137.90 nM) and MMV008956 (average IC50 of 262.30 nM). On average, the laboratory strains were also less susceptible to the three Malaria Box compounds (average IC50 of 162.30 nM) compared to the clinical isolates (average IC50 of 135.40 nM). Additionally, MMV006087 was less potent than artesunate but twice more efficacious than chloroquine against the laboratory strains and clinical isolates. The data from this study validate the potency of MMV006087 and MMV085203 as promising antimalarials worthy of further exploration. This study further substantiates the need to include clinical isolates in antimalarial compound screening activities.
{"title":"MMV006087 is a potent Malaria Box compound against Plasmodium falciparum clinical parasites","authors":"J. Chirawurah, Bridget Adikah, F. Ansah, E. Laryea-Akrong, Harry Danwonno, C. Morang’a, Daniel Dosoo, L. Amenga-Etego, G. Awandare, Y. Aniweh","doi":"10.3389/fddsv.2023.1190471","DOIUrl":"https://doi.org/10.3389/fddsv.2023.1190471","url":null,"abstract":"The emergence of drug-resistant malaria parasites to artemisinin and its partner drugs highlights the need to increase the arsenal of new antimalarials with novel mechanisms of action. To help achieve this aim, this study tested the potency of three Malaria Box compounds (MMV006087, MMV085203, and MMV008956) against five laboratory strains and twenty clinical isolates of Plasmodium falciparum using optimized in vitro growth inhibitory assays. The results were compared to the response from four standard antimalarials-artesunate, chloroquine, mefloquine, and halofantrine. From the results, MMV006087 was the most potent compound with an average IC50 of 22.13 nM compared to MMV085203 (average IC50 of 137.90 nM) and MMV008956 (average IC50 of 262.30 nM). On average, the laboratory strains were also less susceptible to the three Malaria Box compounds (average IC50 of 162.30 nM) compared to the clinical isolates (average IC50 of 135.40 nM). Additionally, MMV006087 was less potent than artesunate but twice more efficacious than chloroquine against the laboratory strains and clinical isolates. The data from this study validate the potency of MMV006087 and MMV085203 as promising antimalarials worthy of further exploration. This study further substantiates the need to include clinical isolates in antimalarial compound screening activities.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45937320","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 : 2023-06-01DOI: 10.3389/fddsv.2023.1176768
Danilo Rosa-Nunes, Danilo B. M. Lucchi, Robert Andreata-Santos, L. Janini, C. Braconi
In the 21st Century, emergence and re-emergence of infectious diseases is significant and has an increasing importance in global concern of public health. Based on the COVID-19 pandemic and recently reported epidemics, most human pathogens originate in zoonosis. Many of such pathogens are related to viruses that have RNA genomes, which can be presented structurally as a single-strand or double-strand. During the last two decades, a timeline of major RNA viruses emergencies can be exemplified, such as Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) in 2003, influenza A virus (H1N1) pdm09 in 2009, Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, Ebola virus (EBOV) in 2013–2016, Zika virus (ZIKV) in 2015 and the SARS-CoV-2 pdm19 in 2019. Even so, prophylactic or therapeutic drugs are unavailable for many RNA viruses circulating. Nonetheless, the COVID-19 pandemic brought considerable scientific advances in accelerating progress regarding prophylaxis, antiviral and drug development, and novel treatments. Regarding RNA virus diseases for humans, arboviruses play an essential and neglected role, constantly reemerging and affecting almost half of the human population, for which no drug has been licensed. Here we review the consolidated RNA viruses’ emergence and re-emergence in the 21st Century through available data. Then, we explored valuable lessons gained during the SARS-CoV-2 pandemic and focused on potential epidemiologic updates, prophylaxis, available treatments, and viral drug inhibitors. Finally, we explore arbovirus’s significance and the ongoing development of effective vaccines, antiviral drugs, and novel therapeutic approaches as strategies to control these neglected tropical diseases (NTD).
{"title":"Lessons that can be learned from the SARS-CoV-2 pandemic and their impact on the prophylaxis and treatment development for neglected tropical arboviruses","authors":"Danilo Rosa-Nunes, Danilo B. M. Lucchi, Robert Andreata-Santos, L. Janini, C. Braconi","doi":"10.3389/fddsv.2023.1176768","DOIUrl":"https://doi.org/10.3389/fddsv.2023.1176768","url":null,"abstract":"In the 21st Century, emergence and re-emergence of infectious diseases is significant and has an increasing importance in global concern of public health. Based on the COVID-19 pandemic and recently reported epidemics, most human pathogens originate in zoonosis. Many of such pathogens are related to viruses that have RNA genomes, which can be presented structurally as a single-strand or double-strand. During the last two decades, a timeline of major RNA viruses emergencies can be exemplified, such as Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) in 2003, influenza A virus (H1N1) pdm09 in 2009, Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, Ebola virus (EBOV) in 2013–2016, Zika virus (ZIKV) in 2015 and the SARS-CoV-2 pdm19 in 2019. Even so, prophylactic or therapeutic drugs are unavailable for many RNA viruses circulating. Nonetheless, the COVID-19 pandemic brought considerable scientific advances in accelerating progress regarding prophylaxis, antiviral and drug development, and novel treatments. Regarding RNA virus diseases for humans, arboviruses play an essential and neglected role, constantly reemerging and affecting almost half of the human population, for which no drug has been licensed. Here we review the consolidated RNA viruses’ emergence and re-emergence in the 21st Century through available data. Then, we explored valuable lessons gained during the SARS-CoV-2 pandemic and focused on potential epidemiologic updates, prophylaxis, available treatments, and viral drug inhibitors. Finally, we explore arbovirus’s significance and the ongoing development of effective vaccines, antiviral drugs, and novel therapeutic approaches as strategies to control these neglected tropical diseases (NTD).","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49066776","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 : 2023-05-24DOI: 10.3389/fddsv.2023.1201419
Natesh Singh, P. Vayer, Shivalika Tanwar, J. Poyet, K. Tsaioun, B. Villoutreix
Finding new drugs usually consists of five main stages: 1) a pre-discovery stage in which basic research is performed to try to understand the mechanisms leading to diseases and propose possible targets (e.g., proteins); 2) the drug discovery stage, during which scientists search for molecules (two main large families, small molecules and biologics) or other therapeutic strategies that interfere or cure the investigated disease or at least alleviate the symptoms; 3) the preclinical development stage that focuses on clarifying the mode of action of the drug candidates, investigates potential toxicity, validates efficacy on various in vitro and in vivo models, and starts evaluate formulation; 4) the clinical stage that investigates the drug candidate in humans; 5) the reviewing, approval and post-market monitoring stage during which the drug is approved or not. In practice, finding new treatments is very challenging. Despite advances in the understanding of biological systems and the development of cutting-edge technologies, the process is still long, costly with a high attrition rate. New approaches, such as artificial intelligence and novel in vitro technologies, are being used in an attempt to rationalize R&D and bring new drugs to patients faster, but several obstacles remain. Our hope is that one day, it becomes possible to rapidly design inexpensive, more specific, more effective, non-toxic, and personalized drugs. This is a goal towards which all authors of this article have devoted most of their careers. Graphical Abstract
{"title":"Drug discovery and development: introduction to the general public and patient groups","authors":"Natesh Singh, P. Vayer, Shivalika Tanwar, J. Poyet, K. Tsaioun, B. Villoutreix","doi":"10.3389/fddsv.2023.1201419","DOIUrl":"https://doi.org/10.3389/fddsv.2023.1201419","url":null,"abstract":"Finding new drugs usually consists of five main stages: 1) a pre-discovery stage in which basic research is performed to try to understand the mechanisms leading to diseases and propose possible targets (e.g., proteins); 2) the drug discovery stage, during which scientists search for molecules (two main large families, small molecules and biologics) or other therapeutic strategies that interfere or cure the investigated disease or at least alleviate the symptoms; 3) the preclinical development stage that focuses on clarifying the mode of action of the drug candidates, investigates potential toxicity, validates efficacy on various in vitro and in vivo models, and starts evaluate formulation; 4) the clinical stage that investigates the drug candidate in humans; 5) the reviewing, approval and post-market monitoring stage during which the drug is approved or not. In practice, finding new treatments is very challenging. Despite advances in the understanding of biological systems and the development of cutting-edge technologies, the process is still long, costly with a high attrition rate. New approaches, such as artificial intelligence and novel in vitro technologies, are being used in an attempt to rationalize R&D and bring new drugs to patients faster, but several obstacles remain. Our hope is that one day, it becomes possible to rapidly design inexpensive, more specific, more effective, non-toxic, and personalized drugs. This is a goal towards which all authors of this article have devoted most of their careers. Graphical Abstract","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41899960","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 : 2023-05-10DOI: 10.3389/fddsv.2023.1185679
Alan H Fairlamb, Susan Wyllie
Understanding the target and mode of action of compounds identified by phenotypic screening can greatly facilitate the process of drug discovery and development. Here, we outline the tools currently available for target identification against the neglected tropical diseases, human African trypanosomiasis, visceral leishmaniasis and Chagas' disease. We provide examples how these tools can be used to identify and triage undesirable mechanisms, to identify potential toxic liabilities in patients and to manage a balanced portfolio of target-based campaigns. We review the primary targets of drugs that are currently in clinical development that were initially identified via phenotypic screening, and whose modes of action affect protein turnover, RNA trans-splicing or signalling in these protozoan parasites.
{"title":"The critical role of mode of action studies in kinetoplastid drug discovery.","authors":"Alan H Fairlamb, Susan Wyllie","doi":"10.3389/fddsv.2023.1185679","DOIUrl":"10.3389/fddsv.2023.1185679","url":null,"abstract":"<p><p>Understanding the target and mode of action of compounds identified by phenotypic screening can greatly facilitate the process of drug discovery and development. Here, we outline the tools currently available for target identification against the neglected tropical diseases, human African trypanosomiasis, visceral leishmaniasis and Chagas' disease. We provide examples how these tools can be used to identify and triage undesirable mechanisms, to identify potential toxic liabilities in patients and to manage a balanced portfolio of target-based campaigns. We review the primary targets of drugs that are currently in clinical development that were initially identified via phenotypic screening, and whose modes of action affect protein turnover, RNA trans-splicing or signalling in these protozoan parasites.</p>","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"3 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7614965/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10173670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-05-09DOI: 10.3389/fddsv.2023.1182146
Irene Tang, L. Schwimmer, Shenda Gu, Wei Wei Prior, Hieu Van Tran, Allan Chan, Anna McClain, C. Fraser, Chunyang Sun, M. Si, Guijiang Wang, Yunxia Zhao, Ning Zhang, Jiayu Fu, Mengxin Liu, Chuanzeng Cao, Shihao Chen
Cell surface molecules PD-L1 and CD47 are potent inhibitors of adaptive and innate anti-cancer immunity. We sought to generate a safe, therapeutic, bispecific antibody specifically targeting, and blocking both PD-L1 and CD47 inhibitory activity. Novel anti-PDL-1 and anti-CD47 antibodies with favorable inhibitory activity, were humanized and constructed into a unique bi-specific antibody intended for clinical use. Previous pre-clinical and clinical studies using anti-CD47 antibodies indicated anemia and thrombocytopenia as potential risks. QL401 is a PD-L1 x CD47 bispecific antibody engineered to reduce effect on red blood cells while retaining potent phagocytic activation of macrophages in vitro and delayed tumor growth in vivo. QL401 comprises three functional components: a PD-L1 binding Fab arm, a CD47 binding scFv arm, and a human IgG4 backbone. The PD-L1 binding arm provides both tumor targeting and blocking of PD-1 for reactivating T cells. The CD47 arm blocks the binding of SIRPα, while the IgG4 Fc retains Fc gamma receptor binding to provide a phagocytic signal. In preclinical efficacy studies, QL401 potently blocked SIRPα to promote phagocytosis of tumor cells with sub-nanomolar potency. In vivo efficacy studies in mouse xenograft tumor models showed QL401 to be comparable or superior to PD-L1 or CD47 monoclonal antibodies alone or in combination. In vitro safety evaluation of QL401 showed significantly reduced binding and phagocytosis of red blood cells, in contrast to CD47 monoclonal antibodies. In addition, QL401 did not induce hemagglutination. In non-human primates, QL401 was well tolerated up to 100 mg/kg without reduction of red blood cells or platelets below the normal range. QL401 is presently in a human phase I safety study.
细胞表面分子PD-L1和CD47是适应性和先天抗癌免疫的有效抑制剂。我们寻求产生一种安全、治疗性、双特异性的抗体，特异性靶向并阻断PD-L1和CD47的抑制活性。将具有良好抑制活性的新型抗pdl -1和抗cd47抗体人源化并构建成一种独特的双特异性抗体，用于临床应用。先前使用抗cd47抗体的临床前和临床研究表明，贫血和血小板减少是潜在的风险。QL401是一种PD-L1 x CD47双特异性抗体，旨在减少对红细胞的影响，同时在体外保持巨噬细胞的有效吞噬激活，并在体内延缓肿瘤生长。QL401由三个功能组件组成:PD-L1结合Fab臂、CD47结合scFv臂和人IgG4骨干。PD-L1结合臂提供肿瘤靶向和阻断PD-1来重新激活T细胞。CD47臂阻断SIRPα的结合，而IgG4 Fc保留Fc γ受体结合以提供吞噬信号。在临床前疗效研究中，QL401有效阻断SIRPα，以亚纳摩尔的效力促进肿瘤细胞的吞噬。在小鼠异种移植肿瘤模型中的体内疗效研究表明，QL401与单独或联合使用的PD-L1或CD47单克隆抗体相当或优于单克隆抗体。体外安全性评价显示，与CD47单克隆抗体相比，QL401对红细胞的结合和吞噬作用显著降低。此外，QL401不诱导血凝。在非人类灵长类动物中，QL401耐受性良好，高达100 mg/kg，红细胞或血小板未减少到正常范围以下。QL401目前正在进行人体I期安全性研究。
{"title":"Generation of a potent anti-PD-L1-CD47 bispecific antibody with a strong therapeutic and safety profile for cancer immunotherapy","authors":"Irene Tang, L. Schwimmer, Shenda Gu, Wei Wei Prior, Hieu Van Tran, Allan Chan, Anna McClain, C. Fraser, Chunyang Sun, M. Si, Guijiang Wang, Yunxia Zhao, Ning Zhang, Jiayu Fu, Mengxin Liu, Chuanzeng Cao, Shihao Chen","doi":"10.3389/fddsv.2023.1182146","DOIUrl":"https://doi.org/10.3389/fddsv.2023.1182146","url":null,"abstract":"Cell surface molecules PD-L1 and CD47 are potent inhibitors of adaptive and innate anti-cancer immunity. We sought to generate a safe, therapeutic, bispecific antibody specifically targeting, and blocking both PD-L1 and CD47 inhibitory activity. Novel anti-PDL-1 and anti-CD47 antibodies with favorable inhibitory activity, were humanized and constructed into a unique bi-specific antibody intended for clinical use. Previous pre-clinical and clinical studies using anti-CD47 antibodies indicated anemia and thrombocytopenia as potential risks. QL401 is a PD-L1 x CD47 bispecific antibody engineered to reduce effect on red blood cells while retaining potent phagocytic activation of macrophages in vitro and delayed tumor growth in vivo. QL401 comprises three functional components: a PD-L1 binding Fab arm, a CD47 binding scFv arm, and a human IgG4 backbone. The PD-L1 binding arm provides both tumor targeting and blocking of PD-1 for reactivating T cells. The CD47 arm blocks the binding of SIRPα, while the IgG4 Fc retains Fc gamma receptor binding to provide a phagocytic signal. In preclinical efficacy studies, QL401 potently blocked SIRPα to promote phagocytosis of tumor cells with sub-nanomolar potency. In vivo efficacy studies in mouse xenograft tumor models showed QL401 to be comparable or superior to PD-L1 or CD47 monoclonal antibodies alone or in combination. In vitro safety evaluation of QL401 showed significantly reduced binding and phagocytosis of red blood cells, in contrast to CD47 monoclonal antibodies. In addition, QL401 did not induce hemagglutination. In non-human primates, QL401 was well tolerated up to 100 mg/kg without reduction of red blood cells or platelets below the normal range. QL401 is presently in a human phase I safety study.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"28 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91355037","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 : 2023-02-27DOI: 10.3389/fddsv.2023.1157688
D. Gambino
COVID-19, the severe acute respiratory syndrome caused by Coronavirus (SARS-CoV-2) and identified for the first time in China in 2019, was recognized in 2020 as a global pandemic by the World Health Organization (Wu et al., 2020; WHO, 2023). Although elder people and all those with underlying medical conditions like cardiovascular disease, diabetes, chronic respiratory disease, or cancer are more likely to develop serious illness, people at any age can become seriously ill or die (WHO, 2023). The efforts of pharmaceutical companies and academia have successfully led to several vaccines against this virus in an unprecedented short period of time. Although vaccines provide protection to healthy people, they could be not effective for immune compromised individuals or those bearing some risky pathological comorbidities. Additionally, mutations could generate viral variants unaffected by currently available vaccines. Therefore, new chemotherapeutic agents are urgently needed for the treatment of SARS-CoV-2 in order to reduce virus dissemination and mortality. Although huge efforts are beingmade since 2020 towards the development of new drugs or the repurposing of already approved drugs to other targets, which would lead to a significant drop in the approval time of these drugs, drugs for the treatment of COVID-19 are not yet a reality (Ashburn and Thor, 2004; Nosengo, 2016; WHO, 2023). At present, there is a clinical need for direct-acting antivirals targeting SARS-CoV-2 to complement existing therapeutic strategies. Accordingly, the aim of this Research Topic of Frontiers in Drug Discovery, Antiinfective Agents, is to collect latest research on the topic focused on:
新冠肺炎是由冠状病毒（SARS-CoV-2）引起的严重急性呼吸综合征，于2019年在中国首次被发现，2020年被世界卫生组织确认为全球大流行（Wu et al.，2020；世界卫生组织，2023）。尽管老年人和所有患有心血管疾病、糖尿病、慢性呼吸道疾病或癌症等潜在疾病的人更有可能患上严重疾病，但任何年龄的人都可能患上重症或死亡（世界卫生组织，2023）。制药公司和学术界的努力在前所未有的短时间内成功研制出了几种针对这种病毒的疫苗。尽管疫苗为健康人提供了保护，但对免疫受损的个体或患有一些危险病理合并症的人可能无效。此外，突变可能产生不受当前可用疫苗影响的病毒变体。因此，迫切需要新的化疗药物来治疗严重急性呼吸系统综合征冠状病毒2型，以减少病毒传播和死亡率。尽管自2020年以来，正在为开发新药或将已批准的药物重新用于其他目标做出巨大努力，这将导致这些药物的批准时间大幅缩短，但治疗新冠肺炎的药物尚未成为现实（Ashburn和Thor，2004；诺森戈，2016；世界卫生组织，2023）。目前，临床上需要针对严重急性呼吸系统综合征冠状病毒2型的直接作用抗病毒药物来补充现有的治疗策略。因此，本研究主题“药物发现的前沿，抗感染剂”的目的是收集关于以下主题的最新研究：
{"title":"Editorial: Development/repurposing of drugs to tackle the multiple variants of SARS-CoV-2","authors":"D. Gambino","doi":"10.3389/fddsv.2023.1157688","DOIUrl":"https://doi.org/10.3389/fddsv.2023.1157688","url":null,"abstract":"COVID-19, the severe acute respiratory syndrome caused by Coronavirus (SARS-CoV-2) and identified for the first time in China in 2019, was recognized in 2020 as a global pandemic by the World Health Organization (Wu et al., 2020; WHO, 2023). Although elder people and all those with underlying medical conditions like cardiovascular disease, diabetes, chronic respiratory disease, or cancer are more likely to develop serious illness, people at any age can become seriously ill or die (WHO, 2023). The efforts of pharmaceutical companies and academia have successfully led to several vaccines against this virus in an unprecedented short period of time. Although vaccines provide protection to healthy people, they could be not effective for immune compromised individuals or those bearing some risky pathological comorbidities. Additionally, mutations could generate viral variants unaffected by currently available vaccines. Therefore, new chemotherapeutic agents are urgently needed for the treatment of SARS-CoV-2 in order to reduce virus dissemination and mortality. Although huge efforts are beingmade since 2020 towards the development of new drugs or the repurposing of already approved drugs to other targets, which would lead to a significant drop in the approval time of these drugs, drugs for the treatment of COVID-19 are not yet a reality (Ashburn and Thor, 2004; Nosengo, 2016; WHO, 2023). At present, there is a clinical need for direct-acting antivirals targeting SARS-CoV-2 to complement existing therapeutic strategies. Accordingly, the aim of this Research Topic of Frontiers in Drug Discovery, Antiinfective Agents, is to collect latest research on the topic focused on:","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45053551","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 : 2023-02-21DOI: 10.3389/fddsv.2023.1082058
Bach-Ngan Nguyen, Florian Tieves, Florian G. Neusius, H. Götzke, L. Schmitt, C. Schwarz
The application of long-chained peptides (+30 aa) and relatively short proteins (<300 aa) has experienced an increasing interest in recent years. However, a reliable production platform is still missing since manufacturing is challenged by inherent problems such as mis-folding, aggregation, and low production yields. And neither chemical synthesis nor available recombinant approaches are effective and efficient. This in particular holds true for disulfide-rich targets where the correct isomer needs to be formed. With the technology Numaswitch, we have now developed a biochemical tool that circumvents existing limitations and serves as first production platform for pepteins, hard-to-be-produced peptides and proteins between 30 and 300 amino acids in length, including disulfide-rich candidates. Numaswitch is based on bifunctional Switchtag proteins that force the high-titer expression of pure inclusion bodies and simultaneously assist in the efficient refolding of pepteins into functional pepteins. Here, we demonstrate the successful application of the Numaswitch platform for disulfide-containing pepteins, such as an antimicrobial fusion peptide, a single-chain variable fragment (scFv), a camelid heavy chain antibody fragment (VHH) and the human epidermal growth factor.
{"title":"Numaswitch, a biochemical platform for the efficient production of disulfide-rich pepteins","authors":"Bach-Ngan Nguyen, Florian Tieves, Florian G. Neusius, H. Götzke, L. Schmitt, C. Schwarz","doi":"10.3389/fddsv.2023.1082058","DOIUrl":"https://doi.org/10.3389/fddsv.2023.1082058","url":null,"abstract":"The application of long-chained peptides (+30 aa) and relatively short proteins (<300 aa) has experienced an increasing interest in recent years. However, a reliable production platform is still missing since manufacturing is challenged by inherent problems such as mis-folding, aggregation, and low production yields. And neither chemical synthesis nor available recombinant approaches are effective and efficient. This in particular holds true for disulfide-rich targets where the correct isomer needs to be formed. With the technology Numaswitch, we have now developed a biochemical tool that circumvents existing limitations and serves as first production platform for pepteins, hard-to-be-produced peptides and proteins between 30 and 300 amino acids in length, including disulfide-rich candidates. Numaswitch is based on bifunctional Switchtag proteins that force the high-titer expression of pure inclusion bodies and simultaneously assist in the efficient refolding of pepteins into functional pepteins. Here, we demonstrate the successful application of the Numaswitch platform for disulfide-containing pepteins, such as an antimicrobial fusion peptide, a single-chain variable fragment (scFv), a camelid heavy chain antibody fragment (VHH) and the human epidermal growth factor.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47786351","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 : 2023-02-10DOI: 10.3389/fddsv.2023.1112992
Dennis A. Hauser, P. Mäser
Introduction: Suramin is one of the pharmacopeia’s most promiscuous drugs. Originally developed for African trypanosomiasis, suramin was also used for onchocerciasis and it has been proposed as an anticancer agent, antiviral drug, therapy for arthritis, autism, and antidote for snake bites. Target proteins of suramin have been described from different species. Here we identify the common motifs among these various targets, aiming to explain the promiscuous nature of suramin. Methods: We have searched for suramin target proteins in the literature and in chemical databases. Applying rigorous inclusion criteria, a list of 44 diverse proteins was assembled with experimental evidence for direct interaction with, and inhibition by, suramin. Hidden Markov model-based target profiling was performed by running the full set of Pfam protein family domains against these proteins. Results: Common denominators were identified by mapping the identified Pfam domains to molecular function gene ontology terms. This in silico pipeline identified nucleotide binding, nucleic acid binding, and binding to divalent cations as the most common denominators of the suramin targets. Discussion: Our results suggest that the extraordinary polypharmacology of suramin may be caused by its ability to inhibit the interaction of proteins with nucleotides or nucleic acids and with divalent cations (Mg2+, Ca2+, Zn2+). Suramin is well known to inhibit nucleotide receptors and nucleic acid-binding enzymes. The association with divalent cations is new and might be key towards the design of better, more selective inhibitors.
{"title":"HMM-based profiling identifies the binding to divalent cations and nucleotides as common denominators of suramin targets","authors":"Dennis A. Hauser, P. Mäser","doi":"10.3389/fddsv.2023.1112992","DOIUrl":"https://doi.org/10.3389/fddsv.2023.1112992","url":null,"abstract":"Introduction: Suramin is one of the pharmacopeia’s most promiscuous drugs. Originally developed for African trypanosomiasis, suramin was also used for onchocerciasis and it has been proposed as an anticancer agent, antiviral drug, therapy for arthritis, autism, and antidote for snake bites. Target proteins of suramin have been described from different species. Here we identify the common motifs among these various targets, aiming to explain the promiscuous nature of suramin. Methods: We have searched for suramin target proteins in the literature and in chemical databases. Applying rigorous inclusion criteria, a list of 44 diverse proteins was assembled with experimental evidence for direct interaction with, and inhibition by, suramin. Hidden Markov model-based target profiling was performed by running the full set of Pfam protein family domains against these proteins. Results: Common denominators were identified by mapping the identified Pfam domains to molecular function gene ontology terms. This in silico pipeline identified nucleotide binding, nucleic acid binding, and binding to divalent cations as the most common denominators of the suramin targets. Discussion: Our results suggest that the extraordinary polypharmacology of suramin may be caused by its ability to inhibit the interaction of proteins with nucleotides or nucleic acids and with divalent cations (Mg2+, Ca2+, Zn2+). Suramin is well known to inhibit nucleotide receptors and nucleic acid-binding enzymes. The association with divalent cations is new and might be key towards the design of better, more selective inhibitors.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46032731","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 : 2023-01-20DOI: 10.3389/fddsv.2023.1087008
Elliasu Y. Salifu, James Abugri, Issahaku A Rashid, F. Osei, Joseph Atia Ayariga
Malaria caused by Plasmodium falciparum, remains one of the most fatal parasitic diseases that has affected nearly a third of the world’s population. The major impediment to the treatment of malaria is the emergence of resistance of the P. falciparum parasite to current anti-malaria therapeutics such as Artemisinin (ART)-based combination therapy (ACT). This has resulted in countless efforts to develop novel therapeutics that will counter this resistance with the aim to control and eradicate the disease. The application of in silico modelling techniques has gained a lot of recognition in antimalarial research in recent times through the identification of biological components of the parasite for rational drug design. In this study we employed various in silico techniques such as the Virtual screening, molecular docking and molecular dynamic simulations to identify potential new inhibitors of biotin acetyl-coenzyme A (CoA) carboxylase and enoyl-acyl carrier reductase, two enzyme targets that play a crucial role in fatty acid synthesis in the Plasmodium parasite. Initially, nine hit compounds were identified for each of the two enzymes from the ZINCPharmer database. Subsequently, all hit compounds bind favourably to the active sites of the two enzymes as well as show excellent pharmacokinetic properties. Three 3) of the hits for the biotin acetyl-coenzyme A (CoA) carboxylase and six 6) of the enoyl-acyl carrier reductase showed good toxicity properties. The compounds were further evaluated based on the Molecular Dynamics simulation that confirmed the binding stability of the compounds to the targeted proteins. Overall, the lead compounds ZINC38980461, ZINC05378039, and ZINC15772056, were identified for acetyl-coenzyme A (CoA) carboxylase whiles ZINC94085628, ZINC93656835, ZINC94080670, ZINC1774609, ZINC94821232 and ZINC94919772 were identified as lead compounds for enoyl-acyl carrier reductase. The identified compounds can be developed as a treatment option for the malaria disease although, experimental validation is suggested for further evaluation of the work.
{"title":"In silico identification of potential inhibitors of acyl carrier protein reductase and acetyl CoA carboxylase of Plasmodium falciparum in antimalarial therapy","authors":"Elliasu Y. Salifu, James Abugri, Issahaku A Rashid, F. Osei, Joseph Atia Ayariga","doi":"10.3389/fddsv.2023.1087008","DOIUrl":"https://doi.org/10.3389/fddsv.2023.1087008","url":null,"abstract":"Malaria caused by Plasmodium falciparum, remains one of the most fatal parasitic diseases that has affected nearly a third of the world’s population. The major impediment to the treatment of malaria is the emergence of resistance of the P. falciparum parasite to current anti-malaria therapeutics such as Artemisinin (ART)-based combination therapy (ACT). This has resulted in countless efforts to develop novel therapeutics that will counter this resistance with the aim to control and eradicate the disease. The application of in silico modelling techniques has gained a lot of recognition in antimalarial research in recent times through the identification of biological components of the parasite for rational drug design. In this study we employed various in silico techniques such as the Virtual screening, molecular docking and molecular dynamic simulations to identify potential new inhibitors of biotin acetyl-coenzyme A (CoA) carboxylase and enoyl-acyl carrier reductase, two enzyme targets that play a crucial role in fatty acid synthesis in the Plasmodium parasite. Initially, nine hit compounds were identified for each of the two enzymes from the ZINCPharmer database. Subsequently, all hit compounds bind favourably to the active sites of the two enzymes as well as show excellent pharmacokinetic properties. Three 3) of the hits for the biotin acetyl-coenzyme A (CoA) carboxylase and six 6) of the enoyl-acyl carrier reductase showed good toxicity properties. The compounds were further evaluated based on the Molecular Dynamics simulation that confirmed the binding stability of the compounds to the targeted proteins. Overall, the lead compounds ZINC38980461, ZINC05378039, and ZINC15772056, were identified for acetyl-coenzyme A (CoA) carboxylase whiles ZINC94085628, ZINC93656835, ZINC94080670, ZINC1774609, ZINC94821232 and ZINC94919772 were identified as lead compounds for enoyl-acyl carrier reductase. The identified compounds can be developed as a treatment option for the malaria disease although, experimental validation is suggested for further evaluation of the work.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43816255","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 : 2023-01-12DOI: 10.3389/fddsv.2022.1093153
M. Argiriadi, Kangwen Deng, D. Egan, Lei Gao, F. Gizatullin, J. Harlan, Denise Karaoglu Hanzatian, W. Qiu, Ruth Villanueva, Andrew Goodearl
LRP8 is a member of the LDLR-like protein family. It is a transport receptor, which can be used in the design of antibodies specific for investigating increasing exposure to therapeutics with respect to the blood brain barrier (BBB). In this study, a LRP8 peptide immunization strategy was implemented to generate antibodies to a specific epitope of the CR1 domain of LRP8 that could enable transport function and cross-react in mice, cynomolgus monkeys and humans. Additionally, a cyclized peptide immunogen was designed to conserve the structural β-hairpin element observed in a previously solved crystal structure of a related CR domain. As a result of this structure-based antigenic design, an LRP8 specific antibody, 11H1, was selected and characterized in ligand binding assays and crystallographic structure determination. The high-resolution structure of the 11H1 Fab complexed to the cyclized CR1 peptide revealed key interactions driving epitope recognition that were confirmed using a site-directed mutagenesis approach. A critical observation was that the identified structural CR1 epitope of 11H1 did not compete with reelin’s recognition of CR1 allowing for simultaneous binding. This was predicted by an in silico ternary model and confirmed by reelin binding data. These simultaneous binding events (11H1/CR1/reelin) could therefore enable the CR1 domain of LRP8, 11H1 and reelin to be used as a “BBB transporter” ternary complex in the design of therapeutic proteins. More importantly, 11H1 showed enhanced brain penetration after systemic intravenous dosing in a mouse study, which confirmed its potential function as BBB transporter for therapeutic proteins.
{"title":"The use of cyclic peptide antigens to generate LRP8 specific antibodies","authors":"M. Argiriadi, Kangwen Deng, D. Egan, Lei Gao, F. Gizatullin, J. Harlan, Denise Karaoglu Hanzatian, W. Qiu, Ruth Villanueva, Andrew Goodearl","doi":"10.3389/fddsv.2022.1093153","DOIUrl":"https://doi.org/10.3389/fddsv.2022.1093153","url":null,"abstract":"LRP8 is a member of the LDLR-like protein family. It is a transport receptor, which can be used in the design of antibodies specific for investigating increasing exposure to therapeutics with respect to the blood brain barrier (BBB). In this study, a LRP8 peptide immunization strategy was implemented to generate antibodies to a specific epitope of the CR1 domain of LRP8 that could enable transport function and cross-react in mice, cynomolgus monkeys and humans. Additionally, a cyclized peptide immunogen was designed to conserve the structural β-hairpin element observed in a previously solved crystal structure of a related CR domain. As a result of this structure-based antigenic design, an LRP8 specific antibody, 11H1, was selected and characterized in ligand binding assays and crystallographic structure determination. The high-resolution structure of the 11H1 Fab complexed to the cyclized CR1 peptide revealed key interactions driving epitope recognition that were confirmed using a site-directed mutagenesis approach. A critical observation was that the identified structural CR1 epitope of 11H1 did not compete with reelin’s recognition of CR1 allowing for simultaneous binding. This was predicted by an in silico ternary model and confirmed by reelin binding data. These simultaneous binding events (11H1/CR1/reelin) could therefore enable the CR1 domain of LRP8, 11H1 and reelin to be used as a “BBB transporter” ternary complex in the design of therapeutic proteins. More importantly, 11H1 showed enhanced brain penetration after systemic intravenous dosing in a mouse study, which confirmed its potential function as BBB transporter for therapeutic proteins.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41635901","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}
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