Novel Immunopharmacological Drugs for the Treatment of Allergic Diseases.

The exponential rise in the prevalence of allergic diseases since the mid-twentieth century has led to a genuine public health emergency and has also fostered major progress in research on the underlying mechanisms and potential treatments. The management of allergic diseases benefits from the biological revolution, with an array of novel immunomodulatory therapeutic and investigational tools targeting players of allergic inflammation at distinct pathophysiological steps. Prominent examples include therapeutic monoclonal antibodies against cytokines, alarmins, and their receptors, as well as small-molecule modifiers of signal transduction mainly mediated by Janus kinases and Bruton's tyrosine kinases. However, the first-line therapeutic options have yet to switch from symptomatic to disease-modifying interventions. Here we present an overview of available drugs in the context of our current understanding of allergy pathophysiology, identify potential therapeutic targets, and conclude by providing a selection of candidate immunopharmacological molecules under investigation for potential future use in allergic diseases.

Identification of benzothiazoles as novel PCSK9 inhibitors.

Proprotein convertase subtilisin kexin type 9 (PCSK9) is a clinically validated target on the treatment of cardiovascular disease (CVD). PCSK9 can regulate the hepatocyte surface low density lipoprotein receptor (LDLR) level by binding to LDLR and leading to their degradation in the lysosome. The clinical use of two monoclonal antibodies (alirocumab and evolocumab, approved in 2015) and one small interfering RNA (inclisiran, approved in 2020) which can inhibit PCSK9 function proved that they are very effective in lowering low density lipoprotein cholesterol (LDL-C). However, the high treatment costs and parenteral administration of these drugs prohibited widespread use and reduced their long-term advantage. Comparatively, small molecule drugs have many incomparable advantages of macromolecules, such as lower treatment cost, more drug administration options, superior pharmacokinetic properties, less adverse immunogenic responses and better affordable production. In this paper, we identified a series of benzothiazoles small molecule PCSK9 inhibitors through extensive screening. The structure and activity relationship (SAR) was summarized to facilitate further optimization. Moreover, the primary mechanism of action of the most potent compound was also investigated.

Catalysts of Healing: A Symphony of Synthesis and Clinical Artistry in Small-Molecule Agents for Breast Cancer Alleviation.

Breast cancer, characterized by its molecular intricacy, has witnessed a surge in targeted therapeutics owing to the rise of small-molecule drugs. These entities, derived from cutting-edge synthetic routes, often encompassing multistage reactions and chiral synthesis, target a spectrum of oncogenic pathways. Their mechanisms of action range from modulating hormone receptor signaling and inhibiting kinase activity, to impeding DNA damage repair mechanisms. Clinical applications of these drugs have resulted in enhanced patient survival rates, reduction in disease recurrence, and improved overall therapeutic indices. Notably, certain molecules have showcased efficacy in drug-resistant breast cancer phenotypes, highlighting their potential in addressing treatment challenges. The evolution and approval of small-molecule drugs have ushered in a new era for breast cancer therapeutics. Their tailored synthetic pathways and defined mechanisms of action have augmented the precision and efficacy of treatment regimens, paving the way for improved patient outcomes in the face of this pervasive malignancy. The present review embarks on a detailed exploration of small-molecule drugs that have secured regulatory approval for breast cancer treatment, emphasizing their clinical applications, synthetic pathways, and distinct mechanisms of action.

Pairwise synthetic cytotoxicity between Paxlovid and 100 frequently prescribed FDA-approved small molecule drugs on liver cells.

Paxlovid is a recent FDA approved specific drug for COVID-19. Extensive prescription of Paxlovid could induce potential synthetic cytotoxicity with drugs. Herein, we aimed to examine pairwise synthetic cytotoxicity between Paxlovid and 100 frequently FDA approved small molecule drugs. Liver cell line HL-7702 or L02 was adopted to evaluate synthetic cytotoxicity between Paxlovid and the 100 small molecule drugs. Inhibitory concentration IC-10 and IC-50 doses for all the 100 small molecule drugs and Paxlovid were experimentally acquired. Then, pairwise synthetic cytotoxicity was examined with the fixed dose IC-10 for each drug. The most 4 significant interactive pairs (2 positively interactive and 2 negatively interactive) were further subjected to molecular docking simulation to reveal the structural modulation with Caspase-8, a key mediator for cell apoptosis.

Phenotypic screening platform identifies statins as enhancers of immune cell-induced cancer cell death.

BACKGROUND: High-throughput screening (HTS) of small molecule drug libraries has greatly facilitated the discovery of new cancer drugs. However, most phenotypic screening platforms used in the field of oncology are based solely on cancer cell populations and do not allow for the identification of immunomodulatory agents. METHODS: We developed a phenotypic screening platform based on a miniaturized co-culture system with human colorectal cancer- and immune cells, providing a model that recapitulates part of the tumor immune microenvironment (TIME) complexity while simultaneously being compatible with a simple image-based readout. Using this platform, we screened 1,280 small molecule drugs, all approved by the Food and Drug Administration (FDA), and identified statins as enhancers of immune cell-induced cancer cell death. RESULTS: The lipophilic statin pitavastatin had the most potent anti-cancer effect. Further analysis demonstrated that pitavastatin treatment induced a pro-inflammatory cytokine profile as well as an overall pro-inflammatory gene expression profile in our tumor-immune model. CONCLUSION: Our study provides an in vitro phenotypic screening approach for the identification of immunomodulatory agents and thus addresses a critical gap in the field of immuno-oncology. Our pilot screen identified statins, a drug family gaining increasing interest as repurposing candidates for cancer treatment, as enhancers of immune cell-induced cancer cell death. We speculate that the clinical benefits described for cancer patients receiving statins are not simply caused by a direct effect on the cancer cells but rather are dependent on the combined effect exerted on both cancer and immune cells.

Potential COVID-19 therapeutic approaches targeting angiotensin-converting enzyme 2; An updated review.

COVID-19 has spread swiftly throughout the world posing a global health emergency. The significant numbers of deaths attributed to this pandemic have researchers battling to understand this new, dangerous virus. Researchers are looking to find possible treatment regimens and develop effective therapies. This study aims to provide an overview of published scientific information on potential treatments, emphasizing angiotensin-converting enzyme II (ACE2) inhibitors as one of the most important drug targets. SARS-CoV-2 receptor-binding domain (RBD); as a viral attachment or entry inhibitor against SARS-CoV-2, human recombinant soluble ACE2; as a genetically modified soluble form of ACE2 to compete with membrane-bound ACE2, and microRNAs (miRNAs); as a negative regulator of the expression of ACE2/TMPRSS2 to inhibit SARS-CoV2 entry into cells, are the potential therapeutic approaches discussed thoroughly in this article. This review provides the groundwork for the ongoing development of therapeutic agents and effective treatments against SARS-COV-2.

Pathogenic sphingosine 1-phosphate pathway in psoriasis: a critical review of its pathogenic significance and potential as a therapeutic target.

Sphingosine-1-phosphate (S1P) is a sphingolipid mediator that exerts a variety of biological functions, including immune, cardiovascular, and neurological regulation as well as tumor promotion, through high-affinity G protein-coupled receptors (S1P1-5). It has been reported that circulating S1P levels remain higher in patients with psoriasis than in healthy individuals and that circulating S1P levels do not decrease after anti-TNF-α treatment in those patients. The S1P-S1PR signaling system plays an important role in inhibiting keratinocyte proliferation, regulating lymphocyte migration, and promoting angiogenesis, thus contributing to the regulation of psoriasis pathogenesis. Here, we review the mechanisms by which S1P-S1PR signaling affects the development of psoriasis and the available clinical/preclinical evidence for targeting S1P-S1PR in psoriasis. S1P-S1PR signaling mechanisms may partially explain the link between psoriasis and its comorbidities. Although the detailed mechanisms remain to be elucidated, S1P may be a new target for future psoriasis remission.

Significance of CD80 as a Prognostic and Immunotherapeutic Biomarker in Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) is the primary cause of death among pulmonary cancer patients. Upregulation of CD80 may interact with cytotoxic T lymphocyte antigen 4 (CTLA4) to promote tumor progression and provide a potential target for biological antitumor therapy. However, the role of CD80 in LUAD is still unclear. To investigate the function of CD80 in LUAD, we collected transcriptomic data from 594 lung samples from The Cancer Genome Atlas of America (TCGA) database, along with the corresponding clinical information. We systematically explored the role of CD80 in LUAD using bioinformatics methods, including GO enrichment analysis, KEGG pathway analysis, Gene Set Enrichment Analysis (GSEA), co-expression analysis, and the CIBERSORT algorithm. Finally, we investigated the differences between the two subgroups of CD80 expression in terms of some drug sensitivity, using the pRRophetic package to screen small molecular drugs for therapeutic use. A predictive model based on CD80 for LUAD patients was successfully constructed. In addition, we discovered that the CD80-based prediction model was an independent prognostic factor. Co-expression analysis revealed 10 CD80-related genes, including oncogenes and immune-related genes. Functional analysis showed that the differentially expressed genes in patients with high CD80 expression were mainly located in immune-related signaling pathways. CD80 expression was also associated with immune cell infiltration and immune checkpoints. Highly expressing patients were more sensitive to several drugs, such as rapamycin, paclitaxel, crizotinib, and bortezomib. Finally, we found evidence that 15 different small molecular drugs may benefit the treatment of LUAD patients. This study found that elevated CD80 pairs could improve the prognosis of LUAD patients. CD80 is likely to be a potential as a prognostic and therapeutic target. The future use of small molecular drugs in combination with immune checkpoint blockade to enhance antitumor therapy and improve prognosis for LUAD patients is promising.

Forward or Backward: Lessons Learned from Small Molecule Drugs Approved by FDA from 2012 to 2022.

At every juncture in history, the design and identification of new drugs pose significant challenges. To gain valuable insights for future drug development, we conducted a detailed analysis of New Molecular Entitiy (NME) approved by the Food and Drug Administration (FDA) from 2012 to 2022 and focused on the analysis of first-in-class (FIC) small-molecules from a perspective of a medicinal chemist. We compared the change of numbers between all the FDA-approved NMEs and FIC, which could be more visual to analyze the changing trend of FIC. To get a more visual change of molecular physical properties, we computed the annual average trends in molecular weight for FIC across various therapeutic fields. Furthermore, we consolidated essential information into three comprehensive databases, which covered the indications, canonical SMILES, structural formula, research and development (R&D) institutions, molecular weight, calculated LogP (CLogP), and route of administration on all the small-molecule pharmaceutical. Through the analysis of the database of 11 years of approvals, we forecast the development trend of NME approval in the future.

Ionic Liquids: Promising Approach for Oral Drug Delivery.

Oral administration is the most preferred route for drug administration in clinic. However, due to unsatisfactory physicochemical properties of drugs and various physiological barriers, the oral bioavailability of most poorly water-soluble and macromolecules drugs is low and the therapeutic effect is unsatisfactory. Ionic liquids (ILs), molten salts with unique properties, show amazing potential for oral delivery. In addition to being able to form active pharmaceutical ingredients based ILs (API-ILs) to overcome drug solubility and polymorphism issues, ILs have also been used to enhance the solubility of poorly soluble drugs, enhance drug stability in the gastrointestinal environment, improve drug permeability in intestinal mucus, and facilitate drug penetration across the intestinal epithelial barrier. Furthermore, ILs were attempted as formulation components to develop novel oral drug delivery systems. This review focus on the application progress of ILs in oral drug delivery and the mechanisms. The challenges and perspectives of the development of ILs-based oral delivery systems are also discussed. This article reviews the latest advances of ionic liquids for oral drug delivery, focusing on the application and related mechanisms of ionic liquids in improving the drug physicochemical properties and enhancing drug delivery across physiological barriers.

New pharmaceuticals approved by FDA in 2020: Small-molecule drugs derived from amino acids and related compounds.

Amino acids (AAs) play an important role in the modern health industry as key synthetic precursors for pharmaceuticals, biomaterials, biosensors, and drug delivery systems. Currently, over 30% of small-molecule drugs contain residues of tailor-made AAs or derived from them amino-alcohols and di-amines. In this review article, we profile 12 AA-derived new pharmaceuticals approved by the FDA in 2020. These newly introduced drugs include Tazverik (epithelioid sarcoma), Gemtesa (overactive bladder), Zeposia (multiple sclerosis), Byfavo (induction and maintenance of procedural sedation), Cu 64 dotatate, and Gallium 68 PSMA-11 (both PET imaging), Rimegepant (acute migraine), Zepzelca (lung cancer), Remdesivir (COVID-19), Amisulpride (nausea and vomiting), Setmelanotide (obesity), and Lonafarnib (progeria syndrome). For each compound, we describe the spectrum of biological activity, medicinal chemistry discovery, and synthetic preparation.

Drug repurposing approach to combating coronavirus: Potential drugs and drug targets.

In the past two decades, three highly pathogenic human coronaviruses severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus, and, recently, SARS-CoV-2, have caused pandemics of severe acute respiratory diseases with alarming morbidity and mortality. Due to the lack of specific anti-CoV therapies, the ongoing pandemic of coronavirus disease 2019 (COVID-19) poses a great challenge to clinical management and highlights an urgent need for effective interventions. Drug repurposing is a rapid and feasible strategy to identify effective drugs for combating this deadly infection. In this review, we summarize the therapeutic CoV targets, focus on the existing small molecule drugs that have the potential to be repurposed for existing and emerging CoV infections of the future, and discuss the clinical progress of developing small molecule drugs for COVID-19.

Bioanalytical strategies in drug discovery and development.

A reliable, rapid, and effective bioanalytical method is essential for the determination of the pharmacokinetic, pharmacodynamic, and toxicokinetic parameters that inform the safety and efficacy profile of investigational drugs. The overall goal of bioanalytical method development is to elucidate the procedure and operating conditions under which a method can sufficiently extract, qualify, and/or quantify the analyte(s) of interest and/or their metabolites for the intended purpose. Given the difference in the physicochemical properties of small and large molecule drugs, different strategies need to be adopted for the development of an effective and efficient bioanalytical method. Herein, we provide an overview of different sample preparation strategies, analytical platforms, as well as procedures for achieving high throughput for bioanalysis of small and large molecule drugs.

Identification of four key prognostic genes and three potential drugs in human papillomavirus negative head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a common tumor worldwide with poor prognosis. The pathogenesis of human papillomavirus (HPV)-positive and HPV-negative HNSCCs differs. However, few studies have considered the HPV status when identifying biomarkers for HNSCC. Thus, the identification of biomarkers for HPV-positive and HPV-negative HNSCCs is urgently needed. METHODS: Three microarray datasets from Gene Expression Omnibus (GEO) were analyzed, and the differentially expressed genes (DEGs) were obtained. Then, functional enrichment pathway analysis was performed and protein-protein interaction (PPI) networks were constructed. The expression of hub genes at both the mRNA and protein level was determined in Oncomine, The Cancer Genome Atlas (TCGA) and the Human Protein Atlas (HPA). In addition, survival analysis of the patient stratified by HPV status and the expression levels of key genes were performed based on TCGA data. The role of AREG, STAG3, CAV1 and C19orf57 in cancer were analyzed through Gene set enrichment analysis (GSEA). The top ten small molecule drugs were identified and the therapeutic value of zonisamide, NVP-AUY922, PP-2 and fostamatinib was further evaluated in six HPV-negative HNSCC cell lines. Finally, the therapeutic value of NVP-AUY922 was tested in vivo based on three HPV-negative HNSCC models, and statistical analysis was performed. RESULTS: In total, 47 DEGs were obtained, 11 of which were identified as hub genes. Biological process analysis indicated that the hub genes were associated with the G1/S transition of the mitotic cell cycle. Survival analysis uncovered that the prognostic value of AREG, STAG3, C19orf57 and CAV1 differed between HPV-positive and HPV-negative patients. Gene set enrichment analysis (GSEA) showed the role of AREG, STAG3 and CAV1 in dysregulated pathways of tumor. Ten small molecules were identified as potential drugs specifically for HPV-positive or HPV-negative patients; three-NVP-AUY922, fostamatinib and PP-2-greatly inhibited the proliferation of six HPV-negative HNSCC cell lines in vitro, and NVP-AUY922 inhibited three HPV-negative HNSCC xenografts in vivo. CONCLUSIONS: In conclusion, AREG, STAG3, C19orf57 and CAV1 are key prognostic factors and potential therapeutic targets in HPV-negative HNSCC. NVP-AUY922, fostamatinib and PP-2 may be effective drugs for HPV-negative HNSCC.

On precision dosing of oral small molecule drugs in oncology.

Personalization of oral small molecule anticancer drug doses based on individual patient blood drug levels, also known as therapeutic drug monitoring (TDM), has the potential to significantly improve the effectiveness of treatment by maximizing drug efficacy and minimize toxicity. However, this option has not yet been widely embraced by the oncology community. Some reasons for this include increased logistical complexity of dose individualization, the lack of clinical laboratories that measure small molecule drug concentrations in support of patient care, and the lack of reimbursement of costs. However, the main obstacle may be the lack of studies clearly demonstrating that monitoring of oral small molecule anticancer drug levels actually improves clinical outcomes. Without unequivocal evidence in support of TDM-guided dose individualization, especially demonstration of improved survival with TDM in randomized controlled trials, wide acceptance of this approach by oncologists and reimbursement by insurance companies is unlikely, and patients may continue to suffer as a result of receiving incorrect drug doses. This article reviews the current status of TDM of oral small molecule drugs in oncology and intends to provide strategic insights into the design of studies for evaluating the utility of TDM in this clinical context.

Potential small-molecule drugs as available weapons to fight novel coronavirus (2019-nCoV): A review.

Since the new coronavirus known as 2019-nCoV (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) has widely spread in Wuhan, China, with severe pneumonia, scientists and physicians have made remarkable efforts to use various options such as monoclonal antibodies, peptides, vaccines, small-molecule drugs and interferon therapies to control, prevent or treatment infections of 2019-nCoV. However, no vaccine or drug has yet been confirmed to completely treat 2019-nCoV. In this review, we focus on the use of potential available small-molecule drug candidates for treating infections caused by 2019-nCoV.

The Era of Janus Kinase Inhibitors for Inflammatory Bowel Disease Treatment.

For a significant proportion of patients with inflammatory bowel disease (IBD), primary non-response and secondary loss of response to treatment remain significant issues. Anti-tumor necrosis factor therapies have been licensed for use in IBD. Other disease-related pathways have been targeted as well, including the interleukin 12/23 axis and lymphocyte tracking. However, the need for parenteral administration and the associated costs of dispensing and monitoring all biologics remain a burden on healthcare systems and patients. Janus kinase inhibitors are small-molecule drugs that can be administered orally and are relatively inexpensive, thus offering an additional option for treating IBD. They have been shown to be effective in patients with ulcerative colitis (UC), but they are less effective in those with Crohn's disease (CD). Nonetheless, given the immune-system-based mechanism of these drugs, their safety profile remains a cause for concern. This article provides an overview of Janus kinase (JAK) inhibitors and new trends in the treatment of IBD.

Selection of Promising Novel Fragment Sized S. aureus SrtA Noncovalent Inhibitors Based on QSAR and Docking Modeling Studies.

Sortase A (SrtA) of Staphylococcus aureus has been identified as a promising target to a new type of antivirulent drugs, and therefore, the design of lead molecules with a low nanomolar range of activity and suitable drug-like properties is important. In this work, we aimed at identifying new fragment-sized starting points to design new noncovalent S. aureus SrtA inhibitors by making use of the dedicated molecular motif, 5-arylpyrrolidine-2-carboxylate, which has been previously shown to be significant for covalent binding SrtA inhibitors. To this end, an in silico approach combining QSAR and molecular docking studies was used. The known SrtA inhibitors from the ChEMBL database with diverse scaffolds were first employed to derive descriptors and interpret their significance and correlation to activity. Then, the classification and regression QSAR models were built, which were used for rough ranking of the virtual library of the synthetically feasible compounds containing the dedicated motif. Additionally, the virtual library compounds were docked into the "activated" model of SrtA (PDB:2KID). The consensus ranking of the virtual library resulted in the most promising structures, which will be subject to further synthesis and experimental testing in order to establish new fragment-like molecules for further development into antivirulent drugs.

Emerging systemic drugs in the treatment of plaque psoriasis.

INTRODUCTION: Psoriasis is a common, chronic inflammatory skin condition that affects 2-3% of the US population and represents a large psychosocial burden for patients. Over the last decade, highly effective targeted therapies for psoriasis have been developed - namely, those targeting interleukin (IL)-17 and IL-23. The success of biologic agents targeting IL-17 and IL-23 underscores the importance of the IL-23/T helper (Th)17 cell axis in psoriasis pathogenesis. Oral small molecule drugs - such as Janus kinase (JAK) inhibitors, tyrosine kinase 2 (TYK2) inhibitors, and fumaric acid esters (FAEs) - are also being investigated for the treatment of psoriasis. AREAS COVERED: This article reviews systemic biologic and oral small molecule drugs currently undergoing clinical trials for the treatment of plaque psoriasis. EXPERT OPINION: Many patients with psoriasis have mild disease, and many with mild disease do not seek medical care for their condition. Many patients with mild disease could be adequately treated with topical treatments and phototherapy; however, adherence and feasibility have often been an issue with these treatment types. There seems to be limited room for development of novel biologics, as the existing ones are extraordinarily safe, effective, and convenient with few injections. Patients would prefer a safe, effective oral treatment; however, JAK inhibitors seem unlikely to fill this role completely.

New Therapeutic Options for Advanced Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC), one of the most common lethal diseases in the world, has a 5-year survival rate of only 7%. Hepatocellular carcinoma has no symptoms in the early stage but obvious symptoms in the late stage, leading to delayed diagnosis and reduced treatment efficacy. In recent years, as the scope of HCC research has increased in depth, the clinical development and application of molecular targeted drugs and immunotherapy drugs have brought new breakthroughs in HCC treatment. Targeted therapy drugs for HCC have high specificity, allowing them to selectively kill tumor cells and minimize damage to normal tissues. At present, these targeted drugs are mainly classified into 3 categories: small molecule targeted drugs, HCC antigen-specific targeted drugs, and immune checkpoint targeted drugs. This article reviews the latest research progress on the targeted drugs for HCC.