Expanding antigen-specific regulatory networks to treat autoimmunity.

A significant number of human immunodeficiency virus (HIV) infections have become resistant to antiretroviral treatment, which means that there is a paramount need for novel drug targets to defeat the virus. Until recently, all HIV drugs inhibited HIV replication by mechanisms operating inside infected cells. In contrast, new antiretroviral drugs operate outside infected cells. Their mechanism of action consists in inhibiting entry of the virus into cells, thereby halting the very first step of HIV replication. Examples of this new class of drugs include entry inhibitors, coreceptor antagonists, and fusion inhibitors. In addition to their novel mechanism of action, this new class of drugs also has potential action against drug-resistant HIV strains, causes minimal adverse effects, and may be administered in a simplified, once-daily dosing regimen. New classes of anti-HIV drugs--and new drugs in existing classes--represent the best hope for people infected with HIV, especially those who have exhausted current therapies.

γ-Aminobutyric acid type A receptors (GABAARs) are the main inhibitory mediators in the central nervous system (CNS). GABAARs are pentameric ligand gated ion channels, and the main subunit composition is usually 2α2βγ, with various isotypes assembled within a set of 19 different subunits. The inhibitory function is mediated by chloride ion movement across the GABAARs, activated by synaptic GABA release, reducing neuronal excitability in the adult CNS. Several studies highlighted the importance of GABA-mediated transmission during neuro-development, and its involvement in different neurological and neurodevelopmental diseases, from anxiety to epilepsy. However, while it is well known how different classes of drugs are able to modulate the GABAARs function (benzodiazepines, barbiturates, neurosteroids, alcohol), up to now little is known about GABAARs and cannabinoids interaction in the CNS. Endocannabinoids and phytocannabinoids are lately emerging as a new class of promising drugs for a wide range of neurological conditions, but their safety as medication, and their mechanisms of action are still to be fully elucidated. In this review, we will focus our attention on two of the most promising molecules (Δ9-tetrahydrocannabinol; Δ9-THC and cannabidiol; CBD) of this new class of drugs and their possible mechanism of action on GABAARs.

ABSTRACTIntroduction: Heart failure (HF) affects approximately 2% of the population worldwide, remaining a major cause of hospitalization and mortality despite innovative therapeutic approaches introduced in the past few decades. Type 2 diabetes mellitus (T2DM) contributes significantly to end-organ damage and HF-related complications and is associated with worse clinical status and increased all-cause and cardiovascular mortality in patients with HF with reduced (HFrEF) or with preserved ejection fraction (HFpEF), compared to HF patients without T2DM. Recently, a novel class of antidiabetic drugs has been introduced: sodium glucose co-trasport-2 inhibitors (SGLT2i). Initially designed for patients with T2DM to reduce kidney blood glucose resorption, SGLT2i rapidly gained attention among HF specialists since they were able to show a beneficial prognostic impact in patients affected by HF and T2DM, even independently from the glycemic control as suggested by the EMPA-REG OUTCOME and CANVAS trials.Areas covered: The present review focuses on the mechanisms and the current clinical evidence supporting the use of SGLT2i in HF patients with T2DM. Moreover, the SGLT2i pharmacokinetic and pharmacodynamic properties will be presented in order to better understand the rationale and the design of the ongoing clinical trials investigating directly the effect of this new class of drugs in patients with HF, even independently from T2DM.Expert opinion: SGLT2i are emerging as an effective and safe therapy for the treatment of T2DM and current evidence has unexpectedly demonstrated a robust cardiovascular protection in HF patients with T2DM. Therefore, ongoing clinical trials are investigating directly the effect of this new class of drugs in patients with HF, even independently from T2DM. However, it is methodologically disappointing that the mechanisms underlying the encouraging results in cardiovascular protection of this drug class are still not fully understood. A better understanding of the pharmacokinetic and pharmacodynamic properties of SGLT2i is necessary in order to better determine the effect of this new class of drugs in patients with HF.

Diabetes and obesity are among the key issues for modern healthcare. Approximately 425 million people worldwide have diabetes, and the number of individuals with overweight or obesity exceeds one-third of the entire human population. This necessitates the search for new therapeutic options for treating these conditions and the improvement of existing treatment regimens. This review discusses both the concepts of “diabetes” and obesity, existing treatment schemes, and a new class of antidiabetic drugs—glucose-dependent insulinotropic peptide receptor agonists and glucagon-like peptide-1, as well as its main representative—tirzepatide. The review presents the history of development, justification of the mechanism of action, and existing clinical studies on tirzepatide, a key representative of this emerging class of drugs. This medication has demonstrated a statistically significant reduction in glycated hemoglobin in patients with diabetes and weight loss in patients with obesity and/ or diabetes compared to several classes of antidiabetic drugs. However, it should be noted that adverse reactions in clinical studies were more frequent in the tirzepatide group, especially at high doses, highlighting the need for an individualized approach when prescribing this medication. Additionally, comparisons were made only with insulin and glucagon-like peptide-1 receptor agonists, indicating the limited clinical significance of these studies. The introduction of tirzepatide into clinical practice may potentially reduce obesity levels and help control the progression of diabetes in many patients, thereby decreasing complications and mortality associated with these conditions.

The locked nucleic acid (LNA) chemistry brings truly stunning affinity and high biostability to the world of nucleic acids. In turn, these features enable the design of shorter-than-usual oligos that exhibit unprecedented potency, good specificity, high biostability, good biodistribution, and low toxicity. Such LNA-oligos have been termed RNA antagonists to signal the strong belief that they will transform antisense therapy into a robust drug platform. It is further expected that this new class of drugs will be compatible with less frequent and more convenient dosing regimens than those currently employed with first generation DNA/sub PS/-oligos (DNA-oligos based on phosphorothioate chemistry). For instance, their enhanced biostability may well enable weekly, or even biweekly, dosing. Likewise, the apparent absence of acute toxicities associated with therapeutically sized DNA/sub PS/-oligos may well enable RNA antagonists to be administered by direct bolus injection by healthcare professionals or even by the patients themselves.

The sodium and glucose co-transporter inhibitors type 2 (SGLT2) comprises a new class of hypoglycemic drugs to control type 2 diabetes mellitus, in an attempt to add new non-existing benefits to the so far arising classes. Regarding this new class of drugs, represented by dapaglifozin, canaglifozin and empaglifozin, it is important to highlight the benefits brought by these medications to combat hyperglycemia with insulin-independent mechanisms that are beyond glucose reduction, such as cardiovascular events prevention, reduction in HbA1c, weight loss and blood pressure lowering. Recently, a relevant study (Empa-Reg) brought hope and set the spotlight on the prevention of cardiac events among diabetic patients, which is the main cause of mortality within this group. However, despite coming out as a good treatment option, SGLT2 inhibitors are under constant clinical research and, as a new drug, it should be carefully carried out regarding the long-term effects of glycosuria and other possible side effects, such as the observed increase in the incidence of bladder, breast cancer and bone fractures, which require further studies. Therefore, these compounds might represent a landmark approach for the treatment of diabetes.

Background: Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are devastating blood cancers associated with 5-year survival rates of ~50% each in adults. We recently developed a new class of polymeric drugs called PAMDs based on the CXCR4 inhibitor AMD3100 (plerixafor). PAMDs have the potential to be more effective and less toxic therapeutics than the standard of care high-dose chemotherapy. We tested one variant (PAMD-Ch17), and found that unlike AMD3100, PAMD-Ch17 has several novel anti-leukemic effects. To understand the potential mechanism(s) for these new activities, we performed the following study. Methods: To test the role of CXCR4 in PAMD-Ch17’s activities, we generated CXCR4 knockout cells via Crispr/Cas9. We used PrestoBlue, 7-AAD, and Annexin V staining to assay viability and apoptosis. To identify pathways deregulated by PAMD-Ch17, we performed whole transcriptomic sequencing (RNA-Seq). To investigate if PAMD-Ch17 mediates its activities by inducing oxidative stress, we performed SeaHorse assays, and dihydroethidium (DHE), Mitosox, and Bodipy C11 staining. To investigate whether PAMD induces programmed cell death pathways, we used ferrostatin and deferoxamine to inhibit ferroptosis, necrostatin-1 against necroptosis, and Z-VAD-FMK against apoptosis. Results: We found that PAMD-Ch17 induces cell death in a dose dependent manner in human AML and ALL cell lines and, mouse primary leukemia cells, but not healthy mouse bone marrow cells. Surprisingly, PAMD-Ch17 induces equivalent levels of cell death in both wild type and CXCR4 knockout Jurkat cells, indicating that the only known target of the polymer is not required for its anti-leukemic effects. By RNA-Seq, we found altered expression of genes related to mitochondrial function, suggesting that PAMD-Ch17 could be targeting the mitochondria. To test this, we performed SeaHorse assays and found that PAMD-Ch17 induces a significant decrease in mitochondrial respiration. Consistent with this, we found that PAMD-Ch17 induces a significant increase in superoxide production, as well as lipid peroxidation. Using inhibitors of programmed cell death pathways, we found that preventing necroptosis, apoptosis, or ferroptosis caused only subtle effects on PAMD-Ch17 induced cell death, implying that the polymer’s anti-leukemic activity is likely not entirely dependent on these pathways. Conclusions: These results indicate that PAMD-Ch17 induces cell death in leukemia cells but not healthy bone marrow via a CXCR4 independent mechanism. We also found that PAMD-Ch17 induces reactive oxygen species, potentially explaining its selectivity for leukemia cells compared to healthy blood cells. Continued investigation of PAMD-Ch17 will not only further development of this new class of drugs, but also provide much needed insight into leukemia biology. Citation Format: Calvin Lam, Jogdeo Chinmay, Ekta Kapoor, Siyuan Tang, Svetlana Romanova, David Oupicky, Katherine Hyde. The polymeric AMD3100 based drug PAMD-Ch17 induces its anti-leukemic effects in a CXCR4 independent mechanism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4710.

Sodium glucose co-transporter (SGLT) inhibitors are a new class of drugs which are used in the pharmacotherapy of Type-II diabetes, which happens to be a major risk factor for developing both micro as well as macro-vascular complications. These drugs inhibit the glucose reabsorption by inhibiting SGLT, which exhibits a novel and promising mechanism of action by promoting the urinary glucose excretion hence providing a basis of therapeutic intervention. Results of SGLT-II inhibitors are very encouraging as there is a significant elevation of GLP-1 level, which forms the basis of relevance in treatment of diabetes. It targets the HbA1C and keeps a check on its levels. It also exerts other positive benefits such as weight loss, reduction in blood glucose levels, reduction in blood pressure and improvement in insulin resistance and β-cell dysfunction: All contributing to effective glycemic control. SGLT inhibition will develop as effective modality as it has the capability of inhibiting reabsorption of greater percentage of filtered glucose load.

Flow cytometric analysis of the molecular mechanisms of immunosuppressive action of the active metabolite of leflunomide and its malononitrilamide analogues in a novel whole blood assay

Scientists are learning how a new class of anticancer drugs carries out its unusual way of fighting cancer. The drugs re-activate genes that normally protect against cancer but have been turned off. But the way the drugs were thought to work didn't explain many of their effects.The research by investigators at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSU CCC-James), shows that the drugs cause the destruction of a protein that helps turn off the protective genes.The findings give a new picture of how the drug, decitabine, works. They also suggest that decitabine will probably not be effective in those patients who are taking medications that interfere with the process that destroys the protein.Decitabine is the most potent member of a new class of drugs known as DNA hypomethylating agents. These new drugs are used in a type of cancer treatment known as epigenetic therapy, which is now undergoing clinical trials testing, particularly for some types of leukemia. The findings are published online in the June issue of the journal Molecular and Cellular Biology.DNA hypomethylating agents fight cancer by reversing a chemical process that turns off tumor-suppressor genes, which normally protect cells from becoming cancerous.That process is known as methylation. It involves the gradual addition of chemical units known as methyl groups to genes. As the methyl groups accumulate, the gene gradually shuts down. Decitabine and other hypomethylating agents work by removing the methyl groups, enabling the gene to become active again.Decitabine stops the methylation process by eliminating a protein known as DNA methyltransferase 1, an enzyme that adds methyl groups to DNA.Until now, researchers believed that decitabine must first be incorporated into the cell's DNA before it can work. The DNA methyltransferase protein was then thought to join tightly with the DNA where the drug is incorporated, rendering the enzyme inactive."But that does not appear to be the case," says study leader Samson T. Jacob, Davis Professor in Cancer Research, professor of molecular and cellular biochemistry and of internal medicine, and co-director of the OSU CCC-James Experimental Therapeutics Program. "The drug can become incorporated into the cell's DNA, but that can take considerable time. In contrast, the drug destroys the transferase protein in cancer cells relatively quickly."Jacob and his colleagues found that, once inside the cell, decitabine triggers a series of chemical reactions known as the proteasomal pathway, which degrades the transferase protein."Now that we know what is happening and how it is happening," Jacob says, "we can begin exploring ways to make this drug more effective."Other OSU researchers involved in this study were Kalpana Ghoshal, who co-led the project; Jharna Datta; Sarmila Majumder; Shoumei Bai; Tasneem Motiwala; and Huban Kutay.Funding from the National Cancer Institute and the National Institute of Environmental Health Sciences supported this research.Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute is one of the nation's leading centers for research on the prevention, detection, diagnosis and treatment of cancer. The OSU CCC-James encompasses six interdisciplinary research programs and includes more than 200 investigators who generate over $95 million annually in external funding. It is a founding member of the National Comprehensive Cancer Network, and OSU's James Cancer Hospital is consistently ranked by U.S. News & World Report as one of America's best cancer hospitals.

In this review we discuss the features of a new class of antiretroviral combinations, namely "Virostatics". Virostatics are characterized by the combination of a drug directly inhibiting virus production (viro), and another drug indirectly inhibiting the virus by reducing cellular proliferation (static). In particular, we will focus on the combination of hydroxyurea and didanosine against HIV-1. Hydroxyurea and didanosine synergize to control viral replication and present with a favorable resistance profile, suppressing several resistant quasi-species. Because virostatics target essential cellular proteins, they exert an immune modulating activity and reduce viral targets (CD4 T cells), possibly with limited immunosuppressive effects. Importantly, a dose-finding clinical study has shown that decreasing the dose of hydroxyurea not only diminishes toxicity but also increases antiviral potency. Therefore, the combination of hydroxyurea and didanosine strikes a balance between viral suppression, drug-related toxicity and viral escape, and could have a role both in induction and maintenance therapy. In this review we would like to appraise what is known about hydroxyurea and didanosine and specifically address the major advantages, i.e. novel mechanism of action leading to a new class of drugs and resistance profile providing durability, as well as the major criticisms of this combination, i.e. toxicity and reasons for prescribing a perceived immune suppressant to immune compromised patients.

For low- and middle-income countries, the forecasted incremental value to society created by a class of new prescription drugs would be a useful criterion to prioritize the licensing, subsidization, and provision of new drugs. We provide a methodology to forecast the value of a new class of drugs, defined as the incremental value obtained in the scenario in which the new class of drugs is available along with existing drugs compared with the scenario of existing drugs only. We forecasted the value created by direct-acting antiviral drugs to treat chronic hepatitis C in India. We conducted a physician survey together with an aggregate multinomial logit model to forecast for each patient type the fraction of physicians who would prescribe the new drug under different scenarios. Value was determined by the monetary equivalent of increased life expectancy, reduced disability, and decreased future infection of others, minus drug cost, all treatment-related costs, and the cost of side effects. We forecasted that the introduction of direct-acting antiviral drugs is likely to create USD11.5 billion of value in India over a 5-year period, based on a 'realistic' assumption about the growth rate of India's per capita GDP. Under 'pessimistic' and 'optimistic' assumptions about the growth rate, the value changes to USD6.5 and 22.5 billion, respectively. There is major value likely to be created by the new direct-acting antiviral drugs in treating hepatitis C in India; this is consistent with the Indian Government's decision to provide the drugs free of cost.

Cancer researchers have long suggested that new targeted drugs may work best when paired with other therapies. In a new study published today in Cancer Research, scientists have taken some of the first steps to demonstrate this synergy in mouse and cell line models. The findings show that two different drugs may work better in a "one-two punch," targeting a cancer development process in two types of cells. The early results are so promising that preliminary testing of the drug combination in humans is now being planned."Anti-angiogenesis" drugs which inhibit vast networks of blood vessels that feed tumors have thus far failed to make the anticipated dramatic impact on targeted tumors when used singly in human clinical studies, say Johns Hopkins Kimmel Cancer Center investigators. Previous evidence by the Hopkins scientists and others suggest that a new class of drugs which helps normalize how DNA is wrapped around a scaffolding of proteins called histones also has secondary effects on limiting blood vessel development."Combining these two types of drugs may have a greater impact on cancer development than using them alone," says Roberto Pili, M.D., assistant professor of oncology at the Kimmel Cancer Center. "Our idea is to attack the way cancers form new blood vessels by disrupting the angiogenesis process in two different cells."Cancer cells inappropriately remove small molecules called acetyl groups from histones, forcing the DNA to remain tightly coiled and restricting gene activation. This error may be reversed by using drugs called histone deacetylase (HDAC) inhibitors to block the enzymes that remove the acetyl groups allowing the DNA to unwrap itself and make necessary gene products.To test the combination, the Hopkins scientists chose an anti-angiogenesis drug (called PTK787/ZK222584) that blocks the effect of a protein called VEGF, for vascular endothelial growth factor, which is responsible for triggering a cascade of cell signals that promote blood vessel formation."Such VEGF inhibitors are known to have most effect on endothelial cells, the bricks and mortar of blood vessels," explains Pili. "However, HDAC inhibitors target both endothelial and epithelial cells, which line organs, and are the origin of many cancers."In this Hopkins study, the VEGF inhibitor combined with an HDAC inhibitor called NVP-LAQ824 reduced the number of endothelial cells in culture dishes by 51 percent, compared with approximately half the effectiveness using the two drugs alone. In mouse models, the combination controlled 60 percent of new blood vessel formation compared to 50 percent using the agents alone.Tumor growth in mice with prostate cancer was reduced by 35 and 75 percent for the VEGF and HDAC inhibitors, respectively. The combination of drugs reduced tumor development by 85 percent.Mice with breast cancer showed similar inhibition of tumors with 54 and 60 percent growth reduction for the VEGF and HDAC inhibitors alone. In combination, the drugs slowed tumor growth by 80 percent.The team also profiled gene activation patterns in tumor and endothelial cells treated with the HDAC inhibitor. They noted additional action on blood vessel development by its ability to decrease activation of several critical angiogenesis-related genes and proteins, including HIF1a (hypoxia inducible factor), VEGF, survivin, angiopoietin-2 and its receptor, Tie-2.Based on these results, the team is planning a clinical trial at the Johns Hopkins Kimmel Cancer Center, sponsored by the National Cancer Institute, using similar VEGF and HDAC inhibitors.The research was funded by the American Cancer Society, the Commonwealth Foundation for Cancer Research, and a Sidney Kimmel Foundation Research Award.David Z. Qian, Ph.D, is the first author on this research and additional participants include Xiaofei Wang, Sushant K. Kachhap, Yukihiko Kato, Yongfeng Wei, and Lu Zhang from Johns Hopkins; and Peter Atadja from the Novartis Institute for Biomedical Research.

This Month in Gastroenterology

Vascular disrupting agents: a new class of drug in cancer therapy