How To Design Selective Ligands for Highly Conserved Binding Sites: A Case Study Using N-Myristoyltransferases as a Model System

A model system of two related enzymes with conserved binding sites, namely N-myristoyltransferase from two different organisms, was studied to decipher the driving forces that lead to selective inhibition in such cases. Using a combination of computational and experimental tools, two different selectivity-determining features were identified. For some ligands, a change in side-chain flexibility appears to be responsible for selective inhibition. Remarkably, this was observed for residues orienting their side chains away from the ligands. For other ligands, selectivity is caused by interfering with a water molecule that binds more strongly to the off-target than to the target. On the basis o…

Individualized Comprehensive Lifestyle Intervention in Patients Undergoing Chemotherapy with Curative or Palliative Intent: Who Participates?

Objective Knowledge about determinants of participation in lifestyle interventions in cancer patients undergoing chemotherapy, particularly with palliative intent, remains poor. The objective of the present study was to identify determinants of participating in a 12 month individualized, comprehensive lifestyle intervention, focusing on diet, physical activity, mental stress and smoking cessation, in cancer patients receiving chemotherapy with curative or palliative intent. The secondary objective was to identify participation determinants 4 months into the study. Methods Newly diagnosed cancer patients starting chemotherapy at the cancer center in Kristiansand/Norway (during a 16 month inc…

Proline-Based Allosteric Inhibitors of Zika and Dengue Virus NS2B/NS3 Proteases

The NS2B/NS3 serine proteases of the Zika and Dengue flaviviruses are attractive targets for the development of antiviral drugs. We report the synthesis and evaluation of a new, proline-based compound class that displays allosteric inhibition of both proteases. The structural features relevant for protease binding and inhibition were determined to establish them as new lead compounds for flaviviral inhibitors. Based on our structure-activity relationship studies, the molecules were further optimized, leading to inhibitors with submicromolar IC50 values and improved lipophilic ligand efficiency. The allosteric binding site in the proteases was probed using mutagenesis and covalent modificati…

Lifestyle changes in cancer patients undergoing curative or palliative chemotherapy: is it feasible?

This study aimed to explore the feasibility of an individualized comprehensive lifestyle intervention in cancer patients undergoing curative or palliative chemotherapy.At one cancer center, serving a population of 180,000, 100 consecutive of 161 eligible newly diagnosed cancer patients starting curative or palliative chemotherapy entered a 12-month comprehensive, individualized lifestyle intervention. Participants received a grouped startup course and monthly counseling, based on self-reported and electronically evaluated lifestyle behaviors. Patients with completed baseline and end of study measurements are included in the final analyses. Patients who did not complete end of study measurem…

New aziridine-based inhibitors of cathepsin L-like cysteine proteases with selectivity for the Leishmania cysteine protease LmCPB2.8

Abstract In the present work a series of aziridine-2,3-dicarboxylate inhibitors of papain-like cysteine proteases was designed, synthesized and tested. The compounds displayed selectivity for the parasitic protozoon Leishmania mexicana cathepsin L-like cysteine protease LmCPB2.8. The computational methods of homology modelling and molecular docking predicted some significant differences in the S2 pocket of LmCPB2.8 and cruzain, a related enzyme from Trypanosoma cruzi. Due to the presence of Tyr209 in LmCPB2.8 rather than Glu208 in cruzain sterically demanding, lipophilic ester groups (inhibitor 7d, 9d, 12d and 14d) are predicted to occupy the S2 pocket of the Leishmania protease, but do not…

Palliative Cancer Patients’ Experiences of Participating in a Lifestyle Intervention Study While Receiving Chemotherapy

Background Lifestyle interventions have promise in terms of their potential health benefits and as an empowerment tool for cancer patients. Nevertheless, documentation of palliative cancer patients experiences of participating in lifestyle interventions remains poor. Objective The objective of this study was to explore how palliative cancer patients experience participation in a feasibility study focusing on multiple lifestyle interventions (physical, nutritional, smoking cessation, and stress management) while receiving chemotherapy. Methods This was a qualitative design with semistructured interviews of 9 palliative cancer patients 3 to 4 months after inclusion to the lifestyle interventi…

Experiences of Patients With Breast Cancer of Participating in a Lifestyle Intervention Study While Receiving Adjuvant Chemotherapy

Background Lifestyle interventions are suggested to reduce the symptom burden and comorbidities in patients with breast cancer and as an empowerment tool. However, undergoing chemotherapy is associated with low compliance to lifestyle recommendations. Importantly, few studies have documented the experiences of patients with breast cancer of participating in a comprehensive lifestyle intervention study while undergoing curative chemotherapy. Objective The aim of this study was to explore the experiences of patients with breast cancer of participating in an individualized comprehensive lifestyle intervention study focusing on diet, physical activity, mental stress management, and smoking cess…

Front Cover: Structure‐Activity Relationships of Benzamides and Isoindolines Designed as SARS‐CoV Protease Inhibitors Effective against SARS‐CoV‐2 (2/2021)

Design, Synthesis and Evaluation of Fluorescent Analogues of Abscisic Acid

A fluorescent analogue of abscisic acid has been prepared by combining (S)‐abscisic acid (ABA) with nitrobenzoxadiazole (NBD) fluorophore using ethanol amine as a linker. Isomerization of the double bond at the side chain of abscisic acid happened during the synthesis. The resulting fluorophore analogues derived from both isomeric compounds entered cells suggesting a wide applicability of the ABA‐NBD conjugates as fluorescent probes to study ABA mechanism of action. The functional properties of the isomeric ABA‐NBD conjugates were tested in vitro, by measuring TNFα expression and nitrite concentration in LPS‐stimulated macrophages and compared with their non‐fluorescent ABA isomers. Rationa…

Identification, Characterization and Synthesis of Natural Parasitic Cysteine Protease Inhibitors – More Potent Falcitidin Analogs

ABSTRACTProtease inhibitors represent a promising therapeutic option for the treatment of parasitic diseases such as malaria and human African trypanosomiasis. Falcitidin was the first member of a new class of inhibitors of falcipain-2, a cysteine protease of the malaria parasite Plasmodium falciparum. Using a metabolomics dataset of 25 Chitinophaga strains for molecular networking enabled identification of over 30 natural analogs of falcitidin. Based on MS/MS spectra, they vary in their amino acid chain length, sequence, acyl residue, and C-terminal functionalization; therefore, they were grouped into the four falcitidin peptide families A-D. The isolation, characterization and absolute st…

Cancer Patients' Long-term Experiences of Participating in a Comprehensive Lifestyle Intervention Study While Receiving Chemotherapy.

Background Lifestyle interventions seem promising with regard to cancer patients' potential for physical and psychological health benefits and as an empowerment tool. Nevertheless, there is a lack of knowledge concerning cancer patients' longer-term experiences of participating in comprehensive lifestyle interventions. Objective The aim of this study was to explore cancer patients' long-term experiences of participating in a 12-month individualized comprehensive lifestyle intervention study focusing on physical activity, diet, smoking cessation, and stress management while receiving curative or palliative chemotherapy. Methods A qualitative design with semistructured interviews of 7 curativ…

Structure‐Activity Relationships of Benzamides and Isoindolines Designed as SARS‐CoV Protease Inhibitors Effective against SARS‐CoV‐2

Abstract Inhibition of coronavirus (CoV)‐encoded papain‐like cysteine proteases (PLpro) represents an attractive strategy to treat infections by these important human pathogens. Herein we report on structure‐activity relationships (SAR) of the noncovalent active‐site directed inhibitor (R)‐5‐amino‐2‐methyl‐N‐(1‐(naphthalen‐1‐yl)ethyl) benzamide (2 b), which is known to bind into the S3 and S4 pockets of the SARS‐CoV PLpro. Moreover, we report the discovery of isoindolines as a new class of potent PLpro inhibitors. The studies also provide a deeper understanding of the binding modes of this inhibitor class. Importantly, the inhibitors were also confirmed to inhibit SARS‐CoV‐2 replication in …

Patient reported outcomes of symptoms and quality of life among cancer patients treated with palliative pelvic radiation: a pilot study

Published version of an article from the journal: BMC Research Notes. Also available from the publisher: http://dx.doi.org/10.1186/1756-0500-4-252 BACKGROUND:There is limited high-quality research investigating the efficacy of palliative radiation (PPR) with regard to symptoms and quality of life (QOL) among cancer patients with pelvic soft tissue tumors. As a result, clinicians are left with mainly retrospective studies, without reliable data on which to base treatment decisions. As a first step of a subsequent analysis of PPR's efficacy, we aimed to determine whether it is feasible to prospectively measure symptoms and QOL among patients treated with PPR. A secondary aim was to explore pa…

BANΔIT: B’‐factor Analysis for Drug Design and Structural Biology

The analysis of B‐factor profiles from X‐ray protein structures can be utilized for structure‐based drug design since protein mobility changes have been associated with the quality of protein‐ligand interactions. With the BANΔIT (B’‐factor analysis and ΔB’ interpretation toolkit), we have developed a JavaScript‐based browser application that provides a graphical user interface for the normalization and analysis of B’‐factor profiles. To emphasize the usability for rational drug design applications, we have analyzed a selection of crystallographic protein‐ligand complexes and have given exemplary conclusions for further drug optimization including the development of a B’‐factor‐supported pha…

Warhead Reactivity Limits the Speed of Inhibition of the Cysteine Protease Rhodesain.

Viral and parasitic pathogens rely critically on cysteine proteases for host invasion, replication, and infectivity. Their inhibition by synthetic inhibitors, such as vinyl sulfone compounds, has emerged as a promising treatment strategy. However, the individual reaction steps of protease inhibition are not fully understood. Using the trypanosomal cysteine protease rhodesain as a medically relevant target, we design photoinduced electron transfer (PET) fluorescence probes to detect kinetics of binding of reversible and irreversible vinyl sulfones directly in solution. Intriguingly, the irreversible inhibitor, apart from its unlimited residence time in the enzyme, reacts 5 times faster than …

Fluorovinylsulfones and -Sulfonates as Potent Covalent Reversible Inhibitors of the Trypanosomal Cysteine Protease Rhodesain: Structure–Activity Relationship, Inhibition Mechanism, Metabolism, and In Vivo Studies

Rhodesain is a major cysteine protease of Trypanosoma brucei rhodesiense, a pathogen causing Human African Trypanosomiasis, and a validated drug target. Recently, we reported the development of α-halovinylsulfones as a new class of covalent reversible cysteine protease inhibitors. Here, α-fluorovinylsulfones/-sulfonates were optimized for rhodesain based on molecular modeling approaches. 2d, the most potent and selective inhibitor in the series, shows a single-digit nanomolar affinity and high selectivity toward mammalian cathepsins B and L. Enzymatic dilution assays and MS experiments indicate that 2d is a slow-tight binder (Ki = 3 nM). Furthermore, the nonfluorinated 2d-(H) shows favorabl…

Interfering with Host Proteases in SARS-CoV-2 Entry as a Promising Therapeutic Strategy

Abstract: Due to its fast international spread and substantial mortality, the coronavirus disease COVID-19 evolved to a global threat. Since there is currently no causative drug against this viral infection available, science is striving for new drugs and other approaches to treat the new disease. Studies have shown that the cell entry of coronaviruses into host cells takes place through the binding of the viral spike (S) protein to cell receptors. Priming of the S protein occurs via hydrolysis by different host proteases. The inhibition of these proteases could impair the processing of the S protein, thereby affecting the interaction with the host-cell receptors and preventing virus cell …

Spiritual Well-being in Patients With Metastatic Colorectal Cancer Receiving Noncurative Chemotherapy

Spiritual well-being (SWB) is an important quality-of-life dimension for cancer patients in the palliative phase. Therefore, it is important for healthcare professionals to recognize the concept of SWB from the patient's point of view. A deeper understanding of how patients experience and reflect upon these issues might influence patient care. The aim of this study was to explore SWB in colorectal cancer patients receiving chemotherapy in the palliative phase. We used a qualitative method of in-depth interviews and a hermeneutic editing approach for the analyses and interpretations. Twenty colorectal cancer patients in the palliative phase, aged 34 to 75 years, were included: 12 patients we…

Cancer patients participating in a lifestyle intervention during chemotherapy greatly over-report their physical activity level: a validation study

Background The short form of the International Physical Activity Questionnaire (IPAQ-sf) is a validated questionnaire used to assess physical activity (PA) in healthy adults and commonly used in both apparently healthy adults and cancer patients. However, the IPAQ-sf has not been previously validated in cancer patients undergoing oncologic treatment. The objective of the present study was to compare IPAQ-sf with objective measures of physical activity (PA) in cancer patients undergoing chemotherapy. Methods The present study was part of a 12-month prospective individualized lifestyle intervention focusing on diet, PA, stress management and smoking cessation in 100 cancer patients undergoing…

From In Silico to Experimental Validation: Tailoring Peptide Substrates for a Serine Protease.

Smart nanocarriers for the transport of drugs to tumor cells are nowadays of great interest for treating cancer. The use of enzymatic stimuli to cleave peptide-based drug nanocapsules for the selective release of nanocapsule cargo in close proximity to tumor cells opens new possibilities in cancer research. In the present work, we demonstrate a methodology for finding and optimizing cleavable substrate sequences by the type II transmembrane serine protease hepsin, which is highly overexpressed in prostate cancer. The design and screening of combinatorial libraries in silico against the binding cavity of hepsin allow the identification of a panel of promising substrates with high-calculated …

Cancer-related fatigue: Patients’ experiences of an intervention at a green care rehabilitation farm

Structure, interdomain dynamics, and pH-dependent autoactivation of pro-rhodesain, the main lysosomal cysteine protease from African trypanosomes

AbstractRhodesain is the lysosomal cathepsin L-like cysteine protease ofT. brucei rhodesiense, the causative agent of Human African Trypanosomiasis. The enzyme is essential for the proliferation and pathogenicity of the parasite as well as its ability to overcome the blood-brain barrier of the host. Lysosomal cathepsins are expressed as zymogens with an inactivating pro-domain that is cleaved under acidic conditions. A structure of the uncleaved maturation intermediate from a trypanosomal cathepsin L-like protease is currently not available. We thus established the heterologous expression ofT. brucei rhodesiensepro-rhodesain inE. coliand determined its crystal structure. The trypanosomal pr…

Increased C-reactive protein implies a poorer stage-specific prognosis in colon cancer.

To characterize the stage-specific prognostic relevance of preoperative systemic inflammatory response, defined by C-reactive protein (CRP), in colon cancer (CC) patients.Data from CC patients operated on from 1998 to 2007 at three hospitals from three different Nordic countries were collected retrospectively from national registries, local databases and/or patient records. Patients with emergency surgery, infection or auto-immune disease were excluded. Associations between clinical or histopathological variables and CRP were assessed. Patients were followed from the date of surgery to death or end of follow-up. Disease-specific survival (DSS) was the main endpoint.In total, 525 patients wi…

Additional file 1: of Cancer patients participating in a lifestyle intervention during chemotherapy greatly over-report their physical activity level: a validation study

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How To Design Selective Ligands for Highly Conserved Binding Sites: A Case Study Using N-Myristoyltransferases as a Model System

A model system of two related enzymes with conserved binding sites, namely N-myristoyltransferase from two different organisms, was studied to decipher the driving forces that lead to selective inhibition in such cases. Using a combination of computational and experimental tools, two different selectivity-determining features were identified. For some ligands, a change in side-chain flexibility appears to be responsible for selective inhibition. Remarkably, this was observed for residues orienting their side chains away from the ligands. For other ligands, selectivity is caused by interfering with a water molecule that binds more strongly to the off-target than to the target. On the basis o…