Anti-norovirus therapeutics: a patent review (2010-2015)

Introduction: Human noroviruses are the primary causative agents of acute gastroenteritis and are a pressing public health burden worldwide. There are currently no vaccines or small molecule therapeutics available for the treatment or prophylaxis of norovirus infections. An improved understanding of norovirus biology, as well as the pathogenic mechanisms underlying the disease, has provided the impetus for a range of intense exploratory drug discovery efforts targeting viral and host factors.

Areas covered: An overview of norovirus inhibitors disclosed in the patent literature (2010-present) and Clinicaltrials.gov is presented. The review is further enriched and supplemented by recent literature reports.

Expert opinion: Seminal discoveries made in recent years, including a better understanding of the pathobiology and life cycle of norovirus, the identification and targeting of multiple viral and host factors, the advent of a replicon system and a small animal model for the preclinical evaluation of lead compounds, and the availability of high resolution X-ray crystal structures that can be utilized in structure-based drug design and lead optimization campaigns, collectively suggest that a small molecule therapeutic and prophylactic for norovirus infection is likely to emerge in the not too distant future.     

Investigational drugs for the treatment of Zika virus infection: a preclinical and clinical update

ABSTRACT

Introduction: The Zika virus (ZIKV) infection results in severe neurological complications and has emerged as a threat to public health worldwide. No drugs or vaccines are available for use in the clinic and the need for novel and effective therapeutic agents is urgent.

Areas covered: This review describes the latest progress of antiviral development for the treatment of ZIKV infection; it primarily focuses on the literature describing 20 potential anti-ZIKV drugs/agents currently being tested in vivo or in clinical trials. The paper also discusses the need for novel ZIKV inhibitors and the critical issues for successful antiviral drug development.

Expert opinion: So far, 20 compounds have been tested in vivo and three in the clinical trials; progressing these compounds to the clinic is a challenge. Novel ZIKV inhibitors that target virus or host factors are urgently needed. Knowledge-driven drug repurposing, structure-based discovery, RNA interference, long noncoding RNAs, miRNAs, and peptide inhibitors may pave the way for the discovery of such novel agents.     

Factor XIa inhibitors: A review of the patent literature

Introduction: Anticoagulants are the mainstay for prevention and/or treatment of thrombotic disorders. Each clinically used anticoagulant is associated with significant adverse consequences, especially bleeding. Factor XIa (FXIa), a key factor involved in the amplification of procoagulation signal, has been suggested as a major target for anticoagulant drug discovery because of reduced risk of bleeding.

Areas covered: Our literature search uncovered dozens of industrial and academic patents on the discovery of novel FXIa/FXI inhibitors. Small peptidomimetics, sulfated glycosaminoglycan mimetics, polypeptides, antisense oligonucleotides, and monoclonal antibodies have been developed as inhibitors of FXIa. Although many agents are in early discovery/development phases, the activity and safety of a few have been evaluated in various animal models and in humans.

Expert opinion: FXIa is a promising drug target for development of effective anticoagulants with limited bleeding complications. Literature reveals a major trend in the number of patent applications over the last three years. These inhibitors exploit different approaches for target inhibition. Allosteric modulation of FXIa and biosynthetic inhibition of FXI are mechanistically unique. Despite initial results in patients undergoing knee anthroplasty as with antisense oligonucleotides, major advances should be realized, particularly with respect to pharmacokinetics, for FXI/FXIa inhibitors to enter the clinic.     

Antiobesity carbonic anhydrase inhibitors: a literature and patent review

Introduction: Obesity is ranked as one of the top 10 global health problems and the major concern deriving from it is the exposure of the population to a vast array of chronic pathologies such as cardiovascular and musculoskeletal disorders, type 2 diabetes, cancer, such as colon, breast and endometrial cancer, together with psychological disorders derived from this condition. The discovery that the clinically used anticonvulsants topiramate (TPM) and zonisamide (ZNS) induced weight loss in obese, epileptic patients, afforded the validation of the mitochondrial carbonic anhydrases (CAs, EC 4.2.1.1) VA and VB as targets for the development of antiobesity drugs.

Areas covered: This review deals with the scientific and patent literature regarding obesity or obesity-related pathologies, being particularly focused on the use of carbonic anhydrase inhibitors (CAI) such as TPM and ZNS which inhibit the de novo lipogenesis.

Expert opinion: There is an urgent need of new drugs for the treatment of obesity. The identification that the mitochondrial CAs are implicated in the de novo lipogenesis allowed to consider selective inhibitors of such enzymes as useful for the development of new antiobesity drugs. Actually TPM was approved 1 year ago for this therapy, whereas ZNS is also an effective such agent. These compounds are the lead molecules in this field and an intense research is on the way in order to develop new compounds based on the selective inhibition of mitochondrial CA isoforms.     

Using Caenorhabditis elegans for antimicrobial drug discovery

Introduction: The number of microorganism strains with resistance to known antimicrobials is increasing. Therefore, there is a high demand for new, non-toxic and efficient antimicrobial agents. Research with the microscopic nematode Caenorhabditis elegans can address this high demand for the discovery of new antimicrobial compounds. In particular, C. elegans can be used as a model host for in vivo drug discovery through high-throughput screens of chemical libraries.

Areas covered: This review introduces the use of substitute model hosts and especially C. elegans in the study of microbial pathogenesis. The authors also highlight recently published literature on the role of C. elegans in drug discovery and outline its use as a promising host with unique advantages in the discovery of new antimicrobial drugs.

Expert opinion: Caenorhabditis elegans can be used, as a model host, to research many diseases, including fungal infections and Alzheimer's disease. In addition, high-throughput techniques for screening chemical libraries can also be facilitated. Nevertheless, C. elegans and mammals have significant differences that both limit the use of the nematode in research and the degree by which results can be interpreted. That being said, the use of C. elegans in drug discovery still holds promise and the field continues to grow, with attempts to improve the methodology already underway.     

cAMP-specific phosphodiesterase inhibitors: promising drugs for inflammatory and neurological diseases

Introduction: PDEs are key enzymes in the adenosine and guanosine cyclic nucleotides (cAMP and cGMP) signaling cascade. Their inhibition increases cyclic nucleotide levels inside the cell. Thus, pharmacological modulation of PDE activity can have profound effects on the function of cells and organ systems throughout the body.

Areas covered: Among the large PDE families, only PDE4, PDE7 and PDE8 are cAMP-specific hydrolyzing enzymes. cAMP is an important second messenger not only by its involvement in a vast number of physiological processes but also by activation of protein kinase A, exchange protein activated by cAMP (Epac) and cAMP response element-binding (CREB) or cyclic nucleotide-gated channels. Clearly, such enzymes represent ideal drug targets for the pharmacological treatment of many pathologies. The discovery and development of small molecules targeting cAMP-specific PDEs reported in the last 5 years is the focus of the present review.

Expert opinion: The first PDE4 inhibitors recently reached the market, having avoided, by different strategies, their dose-limiting side effects (after more than two decades of drug development). Meanwhile, new cAMP-specific PDE7 and PDE8 inhibitors emerged as effective and safe drugs for severe unmet diseases. The therapeutic potential of these inhibitors will be tested in the near future, as many of these drug candidates are ready to start clinical trials.     

Investigational protease inhibitors as antiretroviral therapies

Introduction: Highly Active Antiretroviral Therapy (HAART) has tremendously improved the life expectancy of the HIV-infected population over the past three decades. Protease inhibitors have been one of the major classes of drugs in HAART regimens that are effective in treating HIV. However, the emergence of resistance and cross-resistance against protease inhibitors encourages researchers to develop new PIs with broad-spectrum activity, as well as novel means of enhancing the efficacy of existing PIs.

Areas covered: In this article we discuss recent advances in HIV protease inhibitor (PI) development, focusing on both investigational and experimental agents. We also include a section on pharmacokinetic booster drugs for improved bioavailability of protease inhibitors. Further, we discuss novel drug delivery systems using a variety of nanocarriers for the delivery of PIs across the blood-brain barrier to treat the HIV in the brain.

Expert opinion: We discuss our opinion on the promises and challenges on the development of novel investigational and experimental PIs that are less toxic and more effective in combating drug-resistance. Further, we discuss the future of novel nanocarriers that have been developed to deliver PIs to the brain cells. Although these are promising findings, many challenges need to be overcome prior to making them a viable option.     

Novel approaches for the identification of inhibitors of leishmanial dipeptidylcarboxypeptidase

Introduction: Leishmaniasis imposes a substantial burden of mortality and morbidity affecting 12 million globally and continues to be a neglected tropical disease. Control of the disease is mainly based on chemotherapy, which relies on a handful of drugs with serious limitations. Over the last decade, target-based drug discovery is also being employed in addition to the random screening of compounds. Leishmanial dipeptidylcarboxypeptidase (LDCP), an angiotensin converting enzyme (ACE) related metallopeptidase, has been recently identified as a novel drug target for antileishmanial chemotherapy.

Areas covered: This article examines dipeptidylcarboxypeptidase (DCP) of Leishmania donovani and of other sources from the international literature regarding their biochemical and structural characterization in comparison to mammalian ACE. Furthermore, the author discusses the identification of LdDCP specific inhibitors by virtual screening and their effect on parasite multiplication. Finally, the review looks ahead at areas for further exploration of DCP inhibitors in Leishmania chemotherapy.

Expert opinion: The first step in targeted screening is to identify a suitable drug target and its validation followed by its use in high throughput screening of compounds. Limited studies on LDCP inhibitors have established a good correlation between parasite enzyme inhibition and their biological activity. This suggests that there is a potential for LDCP inhibitors as new antileishmanial drugs.     

Protein tyrosine phosphatase 1B (PTP1B) inhibitors as potential anti-diabetes agents: patent review (2015-2018)

ABSTRACT

Introduction: Protein tyrosine phosphatase 1B (PTP1B) inhibition has been recommended as a crucial strategy to enhance insulin sensitivity in various cells and this fact is supported by human genetic data. PTP1B inhibitors improve the sensitivity of the insulin receptor and have the ability to cure insulin resistance-related diseases. In the latter years, targeting PTP1B inhibitors is being considered an attractive target to treat T2DM and therefore libraries of PTP1B inhibitors are being suggested as potent antidiabetic drugs.

Areas covered: This review provides an overview of published patents from January 2015 to December 2018. The review describes the effectiveness of potent PTP1B inhibitors as pharmaceutical agents to treat type 2 diabetes.

Expert opinion: Enormous developments have been made in PTP1B drug discovery which describes progress in natural products, synthetic heterocyclic scaffolds or heterocyclic hybrid compounds. Various protocols are being followed to boost the pharmacological effects of PTP1B inhibitors. Moreover these new advancements suggest that it is possible to get small-molecule PTP1B inhibitors with the required potency and selectivity. Furthermore, future endevours via an integrated strategy of using medicinal chemistry and structural biology will hopefully result in potent and selective PTP1B inhibitors as well as safer and more effective orally available drugs.     

MCL-1 inhibitors – where are we now (2019)?

ABSTRACT

Introduction: Myeloid cell leukemia-1 (MCL-1) is an anti-apoptotic member of the B-cell lymphoma-2 (BCL-2) family of proteins that regulates apoptosis. Elevated levels of MCL-1 contribute to tumorigenesis and resistance, not only to conventional chemotherapies but also to targeted therapies, including the BCL-2 selective inhibitor venetoclax. Accordingly, researchers in both the pharmaceutical industry and academia have been actively seeking MCL-1 inhibitors in the quest for new anti-cancer drugs.

Areas covered: This review covers the patent literature on the discovery and development of small-molecule inhibitors of MCL-1 since 2017.

Expert opinion: Pharmacologic inhibition of MCL-1's oncogenic activity has certainly come of age with the discovery of numerous inhibitors spanning a variety of chemotypes that selectively inhibit MCL-1 in the picomolar range and with on-target cell activity. Furthermore, seminal research by Servier has demonstrated for the first time that MCL-1 inhibition is tolerable in animal models of cancer, paving the way for the six Phase 1 clinical trials that are currently underway for hematological malignancies, among other cancers. After more than a decade of research, the hurdles and obstacles are mostly behind us, and uncovering the therapeutic impact of disrupting the protein–protein interactions of MCL-1 in humans is imminent.     

Cathepsin B and L inhibitors: a patent review (2010 - present)

Introduction: Cathepsins play an important role in protein degradation and processing. Aberrant cathepsin B or L is closely associated with many serious diseases such as cancer, osteoporosis and autoimmune disorders. Therefore, development of potent and selective cathepsin B and L inhibitors has aroused much attention in recent years. Although several classes of cathepsin inhibitors are presently available, there are still some problems to solve, such as broad-spectrum inhibition to protease, specially cysteine proteases, which lead to unpredictable side effects in clinical trials. Therefore, it is very necessary to discovery new scaffolds and new application of cathepsin B and L inhibitors for developing therapeutic agents for treating diseases mediated by cathepsin B or L.

Areas covered: This updated review summarizes new patents on cathepsin B and L inhibitors from 2010 to present.

Expert opinion: The review gives the latest development in the area of inhibitors of cathepsin B and L, which have been considered key therapeutic targets for the development of drugs treating related diseases. This review puts emphasis on the discovery of novel small molecule inhibitors of cathepsin B and L, as well as their new application as new therapeutic agents.     

Human pluripotent stem cells as tools for neurodegenerative and neurodevelopmental disease modeling and drug discovery

Introduction: Although intensive efforts have been made, effective treatments for neurodegenerative and neurodevelopmental diseases have not been yet discovered. Possible reasons for this include the lack of appropriate disease models of human neurons and a limited understanding of the etiological and neurobiological mechanisms. Recent advances in pluripotent stem cell (PSC) research have now opened the path to the generation of induced pluripotent stem cells (iPSCs) starting from somatic cells, thus offering an unlimited source of patient-specific disease-relevant neuronal cells.

Areas covered: In this review, the authors focus on the use of human PSC-derived cells in modeling neurological disorders and discovering of new drugs and provide their expert perspectives on the field.

Expert opinion: The advent of human iPSC-based disease models has fuelled renewed enthusiasm and enormous expectations for insights of disease mechanisms and identification of more disease-relevant and novel molecular targets. Human PSCs offer a unique tool that is being profitably exploited for high-throughput screening (HTS) platforms. This process can lead to the identification and optimization of molecules/drugs and thus move forward new pharmacological therapies for a wide range of neurodegenerative and neurodevelopmental conditions. It is predicted that improvements in the production of mature neuronal subtypes, from patient-specific human-induced pluripotent stem cells and their adaptation to culture, to HTS platforms will allow the increased exploitation of human pluripotent stem cells in drug discovery programs.     

New methods for multiple sclerosis drug discovery

Introduction: MS is a heterogeneous disorder that requires the development of better diagnostics to identify disease subtypes enabling appropriate therapeutic intervention at an early stage of the disease. Accumulating evidence indicates that members of the inhibitor of apoptosis (IAP) family play an important role in the pathogenesis of MS by reducing the apoptotic elimination of autoreactive immune cells.

Areas covered: The authors describe improved animal modeling strategies to identify compounds that have immunomodulatory, neurorestorative and neuroprotective properties. In addition, the authors propose new approaches to better model cognitive dysfunction in MS, which will aid the development of novel therapeutics for this complex disorder. The paper provides the reader with an appreciation for the diagnostic and therapeutic potential of apoptosis-related proteins for MS.

Expert opinion: Recent evidence suggests that increased resistance of autoreactive immune cells to apoptotic elimination is a contributing factor to both disease susceptibility and progression in MS. This occurs, at least in part, because of elevated levels of the IAP family of anti-apoptotic genes that display distinct expression profiles associated with different subtypes of MS. The authors believe that the detection and targeting of members of the IAP family can provide better drugs for MS. Particularly, the authors feel that the overexpression of IAPs in animal models can provide novel insights into MS for both its pathogenesis and the discovery of new lead compounds.     

Emerging therapies for hepatitis C virus

Importance of the field: Currently, 170 million people worldwide are affected by the HCV. Chronic HCV infection is amongst the leading causes of chronic liver disease and its complications such as cirrhosis and hepatocellular carcinoma, making it the most common reason for liver transplantation. The current standard of treatment for HCV is pegylated IFN-α plus ribavirin. This treatment, when administered for the standard duration, allows sustained virological response (SVR) in ～ 50% of patients infected with HCV and about 40% for HCV genotype 1, the most prevalent form of HCV in the US. SVR rates for populations with co-morbidities (patients with chronic renal disease) and certain ethnic backgrounds (African Americans and Hispanics) are lower. Given the high prevalence and relatively low cure rates of current antiviral therapy, the burden of HCV is enormous.

Areas covered in this review: Faced with this urgent and growing medical need, research into novel therapeutic compounds for the treatment of HCV is a rapidly growing industry. Several novel compounds are in advanced stages of clinical development, such as HCV protease inhibitors (particularly those against NS3-4A protease), HCV polymerase inhibitors (including both nucleoside and non-nucleoside analogs) and cyclophilin inhibitors.

What the reader will gain: HCV treatment has seen many advances in the last decade and the discovery process has been fraught with both successes and disappointments. Through a process of rigorous research, the current late stage novel HCV therapeutics seem to have overcome some of the obstacles met by their early predecessors and offer the promise of meeting the shortfalls of the current standard of treatment.

Take home message: Data from clinical trials are encouraging and suggest that combination therapies of these novel agents may have the potential to shorten treatment duration and increase viral clearance when used in conjunction with pegylated IFN-α and ribavirin.     

Discovery methodology for the development of direct factor VIIa inhibitors

Introduction: Heparin and warfarin have historically been the only antithrombotics available. Recently, however, newer anticoagulants have been developed. Factor VIIa (fVIIa) inhibitors represent one of the new and potentially exciting classes of anticoagulants currently under development. Indeed, several methodologies have been used to develop fVIIa inhibitors.

Areas covered: The authors highlight some of the methologies applied for the discovery of fVIIa inhibitors including phage display, isolation of endogenous peptides from hematophagous animals and the use of the 1,5-benzothiazepine molecular scaffolds and screens of large chemical libraries previously used to identify other serine protease inhibitors. Although these screens were intended to identify thrombin and factor Xa inhibitors, the compounds often had concomitant fVIIa activity. The authors also discuss the utilization of medical chemistry techniques for the discovery of these compounds.

Expert opinion: FVIIa inhibitors represent a viable option for the development of new anticoagulants. There are theoretical advantages that fVIIa inhibitors may possess over existing anticoagulants and highly specific inhibitors that possess oral bioavailability and low bleeding risk may succeed.     

The efficacy and safety of telaprevir – a new protease inhibitor against hepatitis C virus

Importance of the field: Hepatitis C virus (HCV) is the main agent of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma in the western world. It affects more than 170 million people worldwide. HCV treatment, based on the combination of Peg-interferon and ribavirin, is effective in about 50% of treated patients. Therefore, there is a need to develop new drugs active against HCV.

Areas covered in this review: Data were obtained by searching for all full articles on Medline and abstracts presented at major international congresses on viral hepatitis.

What the reader will gain: A review of clinical data about the efficacy and safety of telaprevir (VX-950), the HCV protease inhibitor that is in the most advanced phase of clinical development.

Take home message: Telaprevir has an acceptable pharmacokinetic profile and seems to be a potent antiviral drug against HCV, although, owing to a low genetic barrier, resistant variants emerge within a few days when used in monotherapy, thereby decreasing its efficacy. Consequently, telaprevir has been combined with pegylated-interferon and ribavirin in clinical trials. This triple combination is more effective but has a higher rate of adverse events (notably rash) than the standard of care, despite the shorter duration of therapy.     

Emerging concepts and approaches for chemokine-receptor drug discovery

Importance of the field: Chemokine receptors are most noted for their role in cell migration. However, inappropriate utilization or regulation of these receptors is implicated in many inflammatory diseases, cancer and HIV, making them important drug targets.

Areas covered in this review: Allostery, oligomerization and ligand bias are presented as they pertain to chemokine receptors and their associated pathologies. Specific examples of each are described from the recent literature and their implications are discussed in terms of drug discovery efforts targeting chemokine receptors.

What the reader will gain: Insight into the expanding view of the multitude of pharmacological variables that need to be considered or that may be exploited in chemokine receptor drug discovery.

Take home message: Since 2007, two drugs targeting chemokine receptors have been approved by the FDA, Maraviroc for preventing HIV infection and Mozobil^? for hematopoietic stem cell mobilization. While these successes permit optimism for chemokine receptors as drug targets, only recently has the complexity of this system begun to be appreciated. The concepts of allosteric inhibitors, biased ligands and functional selectivity raise the possibility that drugs with precisely-defined properties can be developed. Other complexities such as receptor oligomerization and tissue-specific functional states of receptors also offer opportunities for increased target and response specificity, although it will be more challenging to translate these ideas into approved therapeutics compared to traditional approaches.     

BRAF and MEK inhibitors in pediatric glioma: new therapeutic strategies,new toxicities

Introduction: BRAF mutation was initially reported in metastatic melanomas, and more recently in a variety of human cancers. BRAF acts as a down-stream effector of growth factor signaling leading to cell cycle progression, proliferation and survival. Development of selective inhibitors of BRAF has improved the survival of patients with melanoma and offers potential new therapeutic strategy in children with BRAF-mutant glioma.

Areas covered: Mechanisms of resistance to BRAF inhibitors have recently been described as due to the paradoxical activation of the MAPK pathway. Combination therapy with BRAF and MEK inhibition has proved capable of overcoming the resistance with effective results in patients with melanoma. Prospective studies in pediatric glioma are warranted. Combination therapy has a different toxicity profile compared to BRAF inhibitor alone. Herein we review the state-of-the-art of toxicities associated with these agents, with a special focus on children.

Expert opinion: Some toxicities appear more specific to adults, due to a combination of factors, such as patient age and predisposing risk factors. Moreover, it is recommended that the co-administration of BRAF inhibitors and drugs metabolized by the cytochrome P450 system in the liver be avoided, as this can lead to significant complications secondary to pharmacological interactions.     

Applications of computer-aided approaches in the development of hepatitis C antiviral agents

Introduction: Hepatitis C virus (HCV) is a global health problem that causes several chronic life-threatening liver diseases. The numbers of people affected by HCV are rising annually. Since 2011, the FDA has approved several anti-HCV drugs; while many other promising HCV drugs are currently in late clinical trials.

Areas covered: This review discusses the applications of different computational approaches in HCV drug design.

Expert opinion: Molecular docking and virtual screening approaches have emerged as a low-cost tool to screen large databases and identify potential small-molecule hits against HCV targets. Ligand-based approaches are useful for filtering-out compounds with rich physicochemical properties to inhibit HCV targets. Molecular dynamics (MD) remains a useful tool in optimizing the ligand-protein complexes and understand the ligand binding modes and drug resistance mechanisms in HCV. Despite their varied roles, the application of in-silico approaches in HCV drug design is still in its infancy. A more mature application should aim at modelling the whole HCV replicon in its active form and help to identify new effective druggable sites within the replicon system. With more technological advancements, the roles of computer-aided methods are only going to increase several folds in the development of next-generation HCV drugs.