Frontiers in drug discovery最新文献

{"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}

{"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}

{"title":"The Need for Speed and Efficiency: A Brief Review of Small Molecule Antivirals for COVID-19","authors":"A. C. Puhl, T. Lane, Fabio Urbina, S. Ekins","doi":"10.3389/fddsv.2022.837587","DOIUrl":"https://doi.org/10.3389/fddsv.2022.837587","url":null,"abstract":"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","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45068868","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}

{"title":"Review of Clinical Trials of COVID-19 Vaccination Booster in SARS-CoV-2 Variants Era: To Take It or Not To Take It","authors":"M. Yan, Ming Yang, Ching‐lung Lai","doi":"10.3389/fddsv.2022.858006","DOIUrl":"https://doi.org/10.3389/fddsv.2022.858006","url":null,"abstract":"Since the COVID-19 outbreak in China in 2019, the pandemic has spread globally. There is no definitive cure, but vaccines have greatly protected humans from symptomatic infections and severe complications. However, vaccine efficacy has been greatly reduced by the advent of SARS-CoV-2 variants worldwide. The World Health Organization has classified the variants into two groups: variants of concern (Alpha, Beta, Gamma, Delta, Omicron) and variants of interest (Lambda, Mu). Clinical trials and modifications of vaccines are currently undertaken to improve their clinical efficacies. This is particularly worrying in immunocompromised patients since breakthrough infections with multiple lineages of variants can pose a continuous threat of severe diseases in these vulnerable subjects, though there is no evidence showing immunocompromised patients are at a higher risk of vaccine-associated adverse events. However, there is no consensus on the schedule, benefits, and risks as well as contraindications (both absolute and relative) of receiving booster vaccinations. This review looks into the efficacy and safety of COVID-19 vaccination booster to guide clinical decisions on when and who to receive booster vaccination.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45217968","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}

{"title":"A Mini-Review of the Anticancer Properties of Cryptotanshinone: A Quinoid Diterpene Extracted From the Root of Salvia miotiorrhiza Bunge","authors":"M. Naziri, Arezoo Ghafari, Hoda Mehrabi, Elham Ramezannezhad, Farzaneh Nazari, Arina Ansari, Farhad Nikzad, N. Deravi","doi":"10.3389/fddsv.2022.815017","DOIUrl":"https://doi.org/10.3389/fddsv.2022.815017","url":null,"abstract":"Cancer is among the most life-threatening diseases worldwide. Along with conventional therapies like chemotherapy, surgery, and radiotherapy, alternative treatment approaches such as traditional Chinese medicine have attracted considerable public and scientific interest that could be beneficial for patients diagnosed with cancer. Salvia miltiorrhiza Bunge is greatly beloved for its roots and is extensively applied for various disease therapies, including cancers in traditional Chinese medicine. In this review, we intend to summarize the anti-cancer properties of Cryptotanshinone (CPT), an extract of Danshen (the root of Salvia miltiorrhiza Bunge), on different types of cancer.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"121 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91368838","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}

{"title":"Deep Machine Learning for Computer-Aided Drug Design","authors":"J. Bajorath","doi":"10.3389/fddsv.2022.829043","DOIUrl":"https://doi.org/10.3389/fddsv.2022.829043","url":null,"abstract":"In recent years, deep learning (DL) has led to new scientific developments with immediate implications for computer-aided drug design (CADD). These include advances in both small molecular and macromolecular modeling, as highlighted herein. Going forward, these developments also challenge CADD in different ways and require further progress to fully realize their potential for drug discovery. For CADD, these are exciting times and at the very least, the dynamics of the discipline will further increase.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49241596","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}

{"title":"The grand challenge of discovering new cardiovascular drugs.","authors":"Charles C Hong","doi":"10.3389/fddsv.2022.1027401","DOIUrl":"https://doi.org/10.3389/fddsv.2022.1027401","url":null,"abstract":"Heart disease is the #1 killer worldwide, greater than all cancers combined. This is despite the fact that, in the developed world, there has been a substantial decline in cardiovascular mortality since the mid-20th century (Centers for Disease Control and Prevention (CDC), 1999), driven largely by a reduction in ischemic heart disease (Mensah et al., 2017; Nowbar et al., 2019). This decline is multifactorial, involving a reduction in tobacco use, changes in diet, treatment of hypertension, advances in rapid coronary revascularization, and the advent of β-hydroxy β-methylglutaryl-CoA (HMG-CoA) reductase inhibitors, and P2Y12 ADP receptor antagonists (Arnett et al., 2019). However, with the adoption of the Western diet and lifestyle in the developing world, and the rise in prevalence of cardiometabolic diseases and obesity, there has been an increase in the global burden of cardiovascular diseases (CVD) (Roth et al., 2020) and a stalling of improvements in the United States (Sinatra and Huston, 2020).","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"2 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10134778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9404673","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}

{"title":"Design and Synthesis of Brain Penetrant Glycopeptide Analogues of PACAP With Neuroprotective Potential for Traumatic Brain Injury and Parkinsonism","authors":"Christopher R. Apostol, K. Bernard, Parthasaradhireddy Tanguturi, G. Molnar, M. J. Bartlett, L. Szábo, Chenxi Liu, J. B. Ortiz, Maha Saber, K. Giordano, T. Green, James Melvin, Helena W. Morrison, L. Madhavan, R. Rowe, J. Streicher, M. Heien, T. Falk, R. Polt","doi":"10.3389/fddsv.2021.818003","DOIUrl":"https://doi.org/10.3389/fddsv.2021.818003","url":null,"abstract":"There is an unmet clinical need for curative therapies to treat neurodegenerative disorders. Most mainstay treatments currently on the market only alleviate specific symptoms and do not reverse disease progression. The Pituitary adenylate cyclase-activating polypeptide (PACAP), an endogenous neuropeptide hormone, has been extensively studied as a potential regenerative therapeutic. PACAP is widely distributed in the central nervous system (CNS) and exerts its neuroprotective and neurotrophic effects via the related Class B GPCRs PAC1, VPAC1, and VPAC2, at which the hormone shows roughly equal activity. Vasoactive intestinal peptide (VIP) also activates these receptors, and this close analogue of PACAP has also shown to promote neuronal survival in various animal models of acute and progressive neurodegenerative diseases. However, PACAP’s poor pharmacokinetic profile (non-linear PK/PD), and more importantly its limited blood-brain barrier (BBB) permeability has hampered development of this peptide as a therapeutic. We have demonstrated that glycosylation of PACAP and related peptides promotes penetration of the BBB and improves PK properties while retaining efficacy and potency in the low nanomolar range at its target receptors. Furthermore, judicious structure-activity relationship (SAR) studies revealed key motifs that can be modulated to afford compounds with diverse selectivity profiles. Most importantly, we have demonstrated that select PACAP glycopeptide analogues (2LS80Mel and 2LS98Lac) exert potent neuroprotective effects and anti-inflammatory activity in animal models of traumatic brain injury and in a mild-toxin lesion model of Parkinson’s disease, highlighting glycosylation as a viable strategy for converting endogenous peptides into robust and efficacious drug candidates.","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47903086","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}

{"title":"<i>In silico</i> Immunogenicity Assessment for Sequences Containing Unnatural Amino Acids: A Method Using Existing <i>in silico</i> Algorithm Infrastructure and a Vision for Future Enhancements.","authors":"Aimee E Mattei, Andres H Gutierrez, William D Martin, Frances E Terry, Brian J Roberts, Amy S Rosenberg, Anne S De Groot","doi":"10.3389/fddsv.2022.952326","DOIUrl":"10.3389/fddsv.2022.952326","url":null,"abstract":"<p><p>The <i>in silico</i> prediction of T cell epitopes within any peptide or biologic drug candidate serves as an important first step for assessing immunogenicity. T cell epitopes bind human leukocyte antigen (HLA) by a well-characterized interaction of amino acid side chains and pockets in the HLA molecule binding groove. Immunoinformatics tools, such as the EpiMatrix algorithm, have been developed to screen natural amino acid sequences for peptides that will bind HLA. In addition to commonly occurring in synthetic peptide impurities, unnatural amino acids (UAA) are also often incorporated into novel peptide therapeutics to improve properties of the drug product. To date, the HLA binding properties of peptides containing UAA are not accurately estimated by most algorithms. Both scenarios warrant the need for enhanced predictive tools. The authors developed an <i>in silico</i> method for modeling the impact of a given UAA on a peptide's likelihood of binding to HLA and, by extension, its immunogenic potential. <i>In silico</i> assessment of immunogenic potential allows for risk-based selection of best candidate peptides in further confirmatory <i>in vitro, ex vivo</i> and <i>in vivo</i> assays, thereby reducing the overall cost of immunogenicity evaluation. Examples demonstrating <i>in silico</i> immunogenicity prediction for product impurities that are commonly found in formulations of the generic peptides teriparatide and semaglutide are provided. Next, this article discusses how HLA binding studies can be used to estimate the binding potentials of commonly encountered UAA and \"correct\" <i>in silico</i> estimates of binding based on their naturally occurring counterparts. As demonstrated here, these in vitro binding studies are usually performed with known ligands which have been modified to contain UAA in HLA anchor positions. An example using D-amino acids in relative binding position 1 (P1) of the PADRE peptide is presented. As more HLA binding data become available, new predictive models allowing for the direct estimation of HLA binding for peptides containing UAA can be established.</p>","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"2 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10026553/pdf/nihms-1854666.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9181785","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}

{"title":"Antifungal properties of (2S, 4R)-Ketoconazole sulfonamide analogs.","authors":"Benjamin E Blass,&nbsp;Sumant Puri,&nbsp;Rishabh Sharma,&nbsp;Brian M Day","doi":"10.3389/fddsv.2022.1000827","DOIUrl":"https://doi.org/10.3389/fddsv.2022.1000827","url":null,"abstract":"<p><p>Invasive candidiasis remains a significant health concern, as it is associated with a high mortality risk. In addition, the risk of infection is significantly elevated in immunocompromised patients such as those with HIV, cancer, or those taking imcmunosuppressive drugs as a result of organ transplantation. The majority of these cases are caused by <i>C. albicans</i>, and <i>C. glabrata</i> is the second most common cause. These infections are typically treated using approved antifungal agents, but the rise of drug-resistant fungi is a serious concern. As part of our on-going effort to identify novel antifungal agents, we have studied the <i>in vitro</i> antifungal properties of a series of sulfonamide analogs of (2S, 4R)-Ketoconazole. Herein we report on the <i>in vitro</i> activity against the key fungal pathogens <i>C. albicans</i>, and <i>C. glabrata</i>.</p>","PeriodicalId":73080,"journal":{"name":"Frontiers in drug discovery","volume":"2 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10198183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9514733","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}