Peptide Therapeutics

Publication date: 1 June 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10
Author(s): Thomas Vorherr




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Therapeutic peptides: Historical perspectives, current development trends, and future directions

Publication date: 1 June 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10
Author(s): Jolene L. Lau, Michael K. Dunn
Peptide therapeutics have played a notable role in medical practice since the advent of insulin therapy in the 1920s. Over 60 peptide drugs are approved in the United States and other major markets, and peptides continue to enter clinical development at a steady pace. Peptide drug discovery has diversified beyond its traditional focus on endogenous human peptides to include a broader range of structures identified from other natural sources or through medicinal chemistry efforts. We maintain a comprehensive dataset on peptides that have entered human clinical studies that includes over 150 peptides in active development today. Here we provide an overview of the peptide therapeutic landscape, including historical perspectives, molecular characteristics, regulatory benchmarks, and a therapeutic area breakdown.

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Publication date: 1 June 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10





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Machine learning-enabled discovery and design of membrane-active peptides

Publication date: 1 June 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10
Author(s): Ernest Y. Lee, Gerard C.L. Wong, Andrew L. Ferguson
Antimicrobial peptides are a class of membrane-active peptides that form a critical component of innate host immunity and possess a diversity of sequence and structure. Machine learning approaches have been profitably employed to efficiently screen sequence space and guide experiment towards promising candidates with high putative activity. In this mini-review, we provide an introduction to antimicrobial peptides and summarize recent advances in machine learning-enabled antimicrobial peptide discovery and design with a focus on a recent work Lee et al. Proc. Natl. Acad. Sci. USA 2016;113(48):13588–13593. This study reports the development of a support vector machine classifier to aid in the design of membrane active peptides. We use this model to discover membrane activity as a multiplexed function in diverse peptide families and provide interpretable understanding of the physicochemical properties and mechanisms governing membrane activity. Experimental validation of the classifier reveals it to have learned membrane activity as a unifying signature of antimicrobial peptides with diverse modes of action. Some of the discriminating rules by which it performs classification are in line with existing "human learned" understanding, but it also unveils new previously unknown determinants and multidimensional couplings governing membrane activity. Integrating machine learning with targeted experimentation can guide both antimicrobial peptide discovery and design and new understanding of the properties and mechanisms underpinning their modes of action.

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Editorial Board

Publication date: 1 June 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10





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Novel oxazolxanthone derivatives as a new type of α-glucosidase inhibitor: synthesis, activities, inhibitory modes and synergetic effect

Publication date: Available online 17 May 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Sen-Miao Ding, Tian Lan, Gao-Jie Ye, Jia-Jun Huang, You Hu, Yi-Ran Zhu, Bo Wang
Xanthone derivatives have shown good α-glucosidase inhibitory activity and have drawn increased attention as potential anti-diabetic compounds. In this study, a series of novel oxazolxanthones were designed, synthesized, and investigated as α-glucosidase inhibitors. Inhibition assays indicated that compounds 4–21 bearing oxazole rings exhibited up to 30-fold greater inhibitory activity compared to their corresponding parent compound 1b. Among them, compounds 5–21 (IC50 = 6.3 ± 0.4–38.5 ± 4.6 μM) were more active than 1-deoxynojirimycin (IC50 = 60.2 ± 6.2 μM), a well-known α-glucosidase inhibitor. In addition, the kinetics of enzyme inhibition measured by using Lineweaver–Burk analysis shows that compound 4 is a competitive inhibitor, while compounds 15, 16 and 20 are non-competitive inhibitors. Molecular docking studies showed that compound 4 bound to the active site pocket of the enzyme while compounds 15, 16, and 20 did not. More interestingly, docking simulations reveal that some of the oxazolxanthone derivatives bind to different sites in the enzyme. This prediction was further confirmed by the synergetic inhibition experiment, and the combination of representative compounds 16 and 20 at the optimal ratio of 4:6 led to an IC50 value of 1.9 ± 0.7 μM, better than the IC50 value of 7.1 ± 0.9 μM for compound 16 and 8.6 ± 0.9 μM for compound 20.

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Publication date: 1 June 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10





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Publication date: 1 June 2018
Source:Bioorganic & Medicinal Chemistry, Volume 26, Issue 10





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Design, synthesis and molecular modeling of new 4-phenylcoumarin derivatives as tubulin polymerization inhibitors targeting MCF-7 breast cancer cells

Publication date: Available online 16 May 2018
Source:Bioorganic & Medicinal Chemistry
Author(s): Rasha Z. Batran, Asmaa F. Kassem, Eman M. Abbas, Samia A. El Seginy, Marwa M. Mounier
A new set of 4-phenylcoumarin derivatives was designed and synthesized aiming to introduce new tubulin polymerization inhibitors as anti-breast cancer candidates. All the target compounds were evaluated for their cytotoxic effects against MCF-7 cell line, where compounds 2f, 3a, 3b, 3 f, 7a and 7b, showed higher cytotoxic effect (IC50=4.3-21.2 μg/mL) than the reference drug doxorubicin (IC50= 26.1 μg/mL), additionally, compounds 1 and 6b exhibited the same potency as doxorubicin (IC50= 25.2 and 28.0 μg/mL, respectively). The thiazolidinone derivatives 3a, 3b and 3 f with potent and selective anticancer effects towards MCF-7 cells (IC50 = 11.1, 16.7 and 21.2 μg/mL) were further assessed for tubulin polymerization inhibition effects which showed that the three compounds were potent tubulin polymerization suppressors with IC50 values of 9.37, 2.89 and 6.13 μM, respectively, compared to the reference drug colchicine (IC50= 6.93 μM). The mechanistic effects on cell cycle progression and induction of apoptosis in MCF-7 cells were determined for compound 3a due to its potent and selective cytotoxic effects in addition to its promising tubulin polymerization inhibition potency. The results revealed that compound 3a induced cell cycle cessation at G2/M phase and accumulation of cells in pre-G1 phase and prevented its mitotic cycle, in addition to its activation of caspase-7 mediating apoptosis of MCF-7 cells. Molecular modeling studies for compounds 3a, 3b and 3 f were carried out on tubulin crystallography, the results indicated that the compounds showed binding mode similar to the co-crystalized ligand; colchicine. Moreover, pharmacophore constructed models and docking studies revealed that thiazolidinone, acetamide and coumarin moieties are crucial for the activity. Molecular dynamics (MD) studies were carried out for the three compounds over 100Ps. MD results of compound 3a showed that it reached the stable state after 30Ps which was in agreement with the calculated potential and kinetic energy of compound 3a.

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Assesment of a Noninvasive Breath Test for Diagnosis of Oesophagogastric Cancer

This multicenter validation study examines the accuracy of a breath test that analyzes volatile organic compounds for the diagnosis of esophagogastric cancer among adults in a curative treatment pathway.

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Reliably Quantifying Bone Metastases in Prostate Cancer

Although bone is the most common site of distant metastases in prostate cancer, reliably evaluating the extent of metastatic burden is a challenge and has been a limiting factor for clinical decision making as well as in clinical trials. Although limited in terms of specificity and sensitivity, bone scan remains the most often used imaging modality for diagnosing and following bone metastases in prostate cancer. One of the objectives of the Prostate Cancer Working Group (PCWG) was to establish criteria for progression in the bone, which could help level the playing field among clinical trials when establishing radiographic progression-free survival (PFS). The PCWG criteria have aided in making clinical trial results comparable with each other. However, the difficulty in establishing burden of metastases at baseline and evaluating response and progression with the same level of precision as for visceral and measurable disease has slowed down the speed at which clinical trials are able to report conclusive results. This difficulty has likely delayed the establishment of new therapeutic options and may have prevented some potentially active agents being brought to market and available to patients.

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Screening for Brain Metastases in Patients With Breast Cancer and Non–Small Cell Lung Cancer

This study analyzes the value of magnetic resonance imaging of the brain for patients with cancers that frequently metastasize to the brain.

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Ethics and the Underreporting of Research Biopsies in Clinical Trials

This Viewpoint examines ethical concerns with respect to biopsy procedures performed in clinical trials and proposes a set of recommendations for biopsy results reporting.

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Electronic Alert for Overuse of G-CSF in Patients Hospitalized for Febrile Neutropenia

This study evaluates the efficacy of an alert in the electronic health record to reduce overuse of granulocyte colony-stimulating factor in older patients hospitalized with febrile neutropenia.

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Characteristics of Radiotherapy Trials vs Other Oncological Trials in the Past 10 Years

This analysis examines the characteristics of radiotherapy interventional trials compared with other oncological interventional trials reported in ClinicalTrials.gov from 2007 through 2017.

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Incorporating Function and Cognition Into Mortality Risk Assessment for Acute Myeloid Leukemia

To the Editor We applaud Sorror and colleagues for systematically investigating the association of comorbidities with the risks of mortality in patients with acute myeloid leukemia (AML). As the authors pointed out, more than half of new AML cases are diagnosed in adults aged 60 years and older. The optimal treatment for this vulnerable group is unclear, and practice patterns vary in this population. Comorbid conditions are prevalent in older adults with AML, and prior studies have reported that between 36% and 45% of older patients have significant comorbidities (Hematopoietic Cell Transplantation–Comorbidity Index score of >1). Although the proposed AML composite model is not specific to older adults, it has the potential to help guide oncologists in selecting treatment for this population. Given the evidence supporting the feasibility and utility of comorbidity assessment in AML, a next logical step is to integrate comorbidity screening routinely into multisite AML trials. The burden is low and potential yield is high.

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Assessment of the Automated Bone Scan Index as a Biomarker of mCRPC Survival in Metastatic Prostate Cancer

This secondary analysis of a randomized clinical trial assesses the automated Bone Scan Index as an independent prognostic determinant of overall survival in men with metastatic castration-resistant prostate cancer.

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Incorporating Function and Cognition Into Mortality Risk Assessment for Acute Myeloid Leukemia—Reply

In Reply We read with interest the call by Drs Loh and Klepin for expanding health assessment tools for older patients with newly diagnosed acute myeloid leukemia (AML).

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Improving the Management of Hereditary Angioedema

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Use of direct oral anticoagulants for chronic thromboembolic pulmonary hypertension

OBJECTIVES: Chronic thromboembolic pulmonary hypertension is one of the most prevalent forms of pulmonary hypertension and is a major complication of acute pulmonary embolism. One mainstay of chronic thromboembolic pulmonary hypertension treatment is lifelong anticoagulation. The recent advent of direct oral anticoagulants for acute pulmonary embolism treatment has provided a viable and effective alternative for treating this condition. However, little is known about the efficacy of this new class of drugs for treating chronic thromboembolic pulmonary hypertension. We aimed to evaluate the safety and efficacy of direct oral anticoagulants in the treatment of chronic thromboembolic pulmonary hypertension. METHODS: A cohort of chronic thromboembolic pulmonary hypertension patients who initiated treatment with direct oral anticoagulants between June 2015 and November 2016 were enrolled in this study. RESULTS: Sixteen patients used rivaroxaban, three used dabigatran and one used apixaban for a mean follow-up of 20.9 months. The mean age was 51 years, and eighteen patients were classified as functional class II/III. Eight patients underwent a pulmonary endarterectomy and exhibited clinical, hemodynamic and functional improvement and currently continue to use direct oral anticoagulants. No episode of venous thromboembolism recurrence was identified during the follow-up period, but there was one episode of major bleeding after a traumatic fall. CONCLUSIONS: Although direct oral anticoagulants appear to be a safe and effective alternative for treating chronic thromboembolic pulmonary hypertension, larger studies are needed to support their routine use.

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