Current challenges in the discovery of treatments against Mayaro fever.

INTRODUCTION: Mayaro fever is an emerging viral disease that manifests as an acute febrile illness. The disease is self-limiting, however joint pain can persist for months leading to chronic arthralgia. There is no specific treatment available, which ultimately leads to socioeconomic losses in populations at risk as well as strains to the public health systems. AREAS COVERED: We reviewed the candidate treatments proposed for Mayaro virus (MAYV) infection and disease, including antiviral compounds targeting viral or host mechanisms, and pathways involved in disease development and pathogenicity. We assessed compound screening technologies and experimental infection models used in these studies and indicated the advantages and limitations of available technologies and intended therapeutic strategies. EXPERT OPINION: Although several compounds have been suggested as candidate treatments against MAYV infection, notably those with antiviral activity, most compounds were assessed only in vitro. Compounds rarely progress toin vivo or preclinical studies, and such difficulty may be associated with limited experimental models. MAYV biology is largely inferred from related alphaviruses and reflected by few studies focusing on target proteins or mechanisms of action for MAYV. Therapeutic strategies targeting pathogenic inflammatory responses have shown potential against MAYV-induced disease in vivo, which might reduce long-term sequelae.

A Comparative Study on the Lysosomal Cation Channel TMEM175 Using Automated Whole-Cell Patch-Clamp, Lysosomal Patch-Clamp, and Solid Supported Membrane-Based Electrophysiology: Functional Characterization and High-Throughput Screening Assay Development.

The lysosomal cation channel TMEM175 is a Parkinson's disease-related protein and a promising drug target. Unlike whole-cell automated patch-clamp (APC), lysosomal patch-clamp (LPC) facilitates physiological conditions, but is not yet suitable for high-throughput screening (HTS) applications. Here, we apply solid supported membrane-based electrophysiology (SSME), which enables both direct access to lysosomes and high-throughput electrophysiological recordings. In SSME, ion translocation mediated by TMEM175 is stimulated using a concentration gradient at a resting potential of 0 mV. The concentration-dependent K+ response exhibited an I/c curve with two distinct slopes, indicating the existence of two conducting states. We measured H+ fluxes with a permeability ratio of PH/PK = 48,500, which matches literature findings from patch-clamp studies, validating the SSME approach. Additionally, TMEM175 displayed a high pH dependence. Decreasing cytosolic pH inhibited both K+ and H+ conductivity of TMEM175. Conversely, lysosomal pH and pH gradients did not have major effects on TMEM175. Finally, we developed HTS assays for drug screening and evaluated tool compounds (4-AP, Zn as inhibitors; DCPIB, arachidonic acid, SC-79 as enhancers) using SSME and APC. Additionally, we recorded EC50 data for eight blinded TMEM175 enhancers and compared the results across all three assay technologies, including LPC, discussing their advantages and disadvantages.

Pre-eclampsia: a Scoping Review of Risk Factors and Suggestions for Future Research Direction.

Abstract: Most of maternal deaths are preventable, and one-quarter of maternal deaths are due to pre-eclampsia and eclampsia. Prenatal screening is essential for detecting and managing pre-eclampsia. However, pre-eclampsia screening is solely based on maternal risk factors and has low (< 5% in the USA) detection rates. This review looks at pre-eclampsia from engineering, public health, and medical points of view. First, pre-eclampsia is defined clinically, and the biological basis of established risk factors is described. The multiple theories behind pre-eclampsia etiology should serve as the scientific basis behind established risk factors for pre-eclampsia; however, African American race does not have sufficient evidence as a risk factor. We then briefly describe predictive statistical models that have been created to improve screening detection rates, which use a combination of biophysical and biochemical biomarkers, as well as aspects of patient medical history as inputs. Lastly, technologies that aid in advancing pre-eclampsia screening worldwide are explored. The review concludes with suggestions for more robust pre-eclampsia research, which includes diversifying study sites, improving biomarker analytical tools, and for researchers to consider studying patients before they become pregnant to improve pre-eclampsia detection rates. Additionally, researchers must acknowledge the systemic racism involved in using race as a risk factor and include qualitative measures in study designs to capture the effects of racism on patients. Lay Summary: Pre-eclampsia is a pregnancy-specific hypertensive disorder that can affect almost every organ system and complicates 2-8% of pregnancies globally. Here, we focus on the biological basis of the risk factors that have been identified for the condition. African American race currently does not have sufficient evidence as a risk factor and has been poorly studied. Current clinical methods poorly predict a patient's likelihood of developing pre-eclampsia; thus, researchers have made statistical models that are briefly described in this review. Then, low-cost technologies that aid in advancing pre-eclampsia screening are discussed. The review ends with suggestions for research direction to improve pre-eclampsia screening in all settings.Overall, we suggest that the future of pre-eclampsia screening should aim to identify those at risk before they become pregnant. We also suggest that the clinical standard of assessing patient risk solely on patient characteristics needs to be reevaluated, that study locations of pre-eclampsia research need to be expanded beyond a few high-income countries, and that low-cost technologies should be developed to increase access to prenatal screening.

Profiling of orthosteric and allosteric group-III metabotropic glutamate receptor ligands on various G protein-coupled receptors with Tag-lite® assays.

Group-III metabotropic glutamate (mGlu) receptors are important synaptic regulators and are potential druggable targets for Parkinson disease, autism and pain. Potential drugs include orthosteric agonists in the glutamate binding extracellular domain and positive allosteric modulators interacting with seven-pass transmembrane domains. Orthosteric agonists are rarely completely specific for an individual group-III mGlu subtype. Furthermore they often fail to pass the blood-brain barrier and they constitutively activate their target receptor. These properties limit the potential therapeutic use of orthosteric agonists. Allosteric modulators are more specific and maintain the biological activity of the targeted receptor. However, they bind in a hydrophobic pocket and this limits their bio-availability and increases possible off-target action. It is therefore important to characterize the action of potential drug targets with a multifaceted and deeply informative assay. Here we aimed at multifaceted deep profiling of the effect of seven different agonists, and seven positive allosteric modulators on 34 different G protein-coupled receptors by a Tag-lite® assay. Our results did not reveal off-target activity of mGlu orthosteric agonists. However, five allosteric modulators had either positive or negative effects on non-cognate G protein-coupled receptors. In conclusion, we demonstrate the power of the Tag-lite® assay for potential drug ligand profiling on G protein-coupled receptors and its potential to identify positive allosteric compounds.

Review on biomimetic affinity chromatography with short peptide ligands and its application to protein purification.

Biomimetic affinity chromatography with short peptide ligands, as a promising bioseparation technique, has great potential to protein separation and purification, which is based on highly specific biological interactions between specially-designed ligands and target proteins. Generally, short peptide ligands with the chain length ranging from two to nine amino acids could be divided into two types, linear peptide ligands and cyclic peptide ligands. To obtain the desired short peptide ligands, rational design strategies could be applied by knowing the 3-dimensional (3D) information of the receptors or just knowing the surface cavities and the active site of the receptors. Subsequently, several technologies could be used to screen the optimal peptide ligands from the designed peptide ligands, such as combinatorial chemistry, phage display, mRNA display and computer-based screening technology. The screening efficiency is dependent on the different technology for individual target proteins. After screening, the chromatographic resin could be prepared by coupling the optimal short peptide ligand onto a matrix with some spacer arms. The suitable matrix and spacer arms are also important to enhance the ability of the peptide ligand for protein purification. With the advantages of high affinity, high adsorption capacity, structural stability, low immunogenicity and low cost, biomimetic affinity chromatography with short peptides as the functional ligands have shown an extensive development and application potentiality to protein purification. In this review, we focused on the strategies of rational designs and screening for short peptide ligands, and some items on the perpetration of new resins and their applications for protein purification would also be discussed.

Global landscape assessment of screening technologies for medicine quality assurance: stakeholder perceptions and practices from ten countries.

BACKGROUND: The spread of substandard and falsified (SF) medical products constitutes a growing global public health concern. Some countries use portable, handheld screening technologies (STs) in the field to accelerate detection of SF medicines and reduce the number of medicine samples that undergo costly and time-consuming confirmatory analysis. METHODS: A multi-country, multi-stakeholder landscape assessment utilizing qualitative methodology was used to examine practices and perceptions related to the use of STs. Qualitative interview guides were designed using the results of a literature review and comprised of open-ended questions with the study participants, who were from national medicine regulatory authorities, pharmaceutical manufacturers, pharmacies, and distributors. Ten geographically and economically diverse countries were selected: Argentina, China, Egypt, India, Jordan, Mexico, Nigeria, Philippines, the United States, and Zimbabwe. Of the completed 53 interviews, 32 were in-person, 16 were phone interviews, and 5 were via written questionnaires. RESULTS: Data analysis shows a wide variation in understanding and usage of STs in different sectors. Virtually all of the study participants indicated a lack of objective, accessible information on STs to advise them on what technologies would be beneficial for their needs. Study participants also described their ideal capabilities of the next generation of STs, including shareable spectral libraries, lower acquisition costs, lesser training requirements, and in-country maintenance and technical support. CONCLUSION: The results and recommendations presented in this article can be used to help regulators communicate and justify their needs to acquire and invest in new STs. There is a need for additional standardized, trustworthy and scientifically sound evaluations of STs, and to support regulators to effectively deploy the most promising technologies. ST manufacturers can take into account some of the limitations of the technologies the interviewees identified in this article, such as a dearth of technologies, which provide quantitative information about the active ingredient, and take steps to address them to better serve their customers. These results and recommendations, can catalyze research and actionable interventions into the development, review, application, and use of STs.

Anti-malarial medicine quality field studies and surveys: a systematic review of screening technologies used and reporting of findings.

BACKGROUND: Assessing the quality of medicines in low-middle income countries (LMICs) relies primarily on human inspection and screening technologies, where available. Field studies and surveys have frequently utilized screening tests to analyse medicines sampled at the point of care, such as health care facilities and medicine outlets, to provide a snap shot of medicine quality in a specific geographical area. This review presents an overview of the screening tests typically employed in surveys to assess anti-malarial medicine quality, summarizes the analytical methods used, how findings have been reported and proposes a reporting template for future studies. METHODS: A systematic search of the peer-reviewed and grey literature available in the public domain (including national and multi-national medicine quality surveys) covering the period 1990-2016 was undertaken. Studies were included if they had used screening techniques to assess the quality of anti-malarial medicines. As no standardized set of guidelines for the methodology and reporting of medicine quality surveys exist, the included studies were assessed for their standard against a newly proposed list of criteria. RESULTS: The titles and abstracts of 4621 records were screened and only 39 were found to meet the eligibility criteria. These 39 studies utilized visual inspection, disintegration, colorimetry and Thin Layer Chromatography (TLC) either as components of the Global Pharma Health Fund (GPHF) MiniLab® or as individual tests. Overall, 30/39 studies reported employing confirmatory testing described in international pharmacopeia to verify the quality of anti-malarials post assessment by a screening test. The authors assigned scores for the 23 criteria for the standard of reporting of each study. CONCLUSIONS: There is considerable heterogeneity in study design and inconsistency in reporting of field surveys of medicine quality. A lack of standardization in the design and reporting of studies of medicine quality increases the risk of bias and error, impacting on the generalizability and reliability of study results. The criteria proposed for reporting on the standard of studies in this review can be used in conjunction with existing medicine quality survey guidelines as a checklist for designing and reporting findings of studies. The review protocol has been registered with PROSPERO (CRD42015026782).

Blood-based screening for bowel cancer may not resolve suboptimal screening participation in Australia.

OBJECTIVE: Emerging blood-based screening technologies for bowel cancer may improve screening participation compared to at-home stool sampling. This study assessed the impact of different screening delivery scenarios with increasing health system interactions on sampling preferences and likelihood of screening participation. METHODS: N=1,561 persons aged 45 to 74 years completed a behavioural survey measuring demographics, readiness to screen, overall collection method preference, and proposed participation in stool and blood methods across four screening scenarios differing in terms of the number of required health system interactions. RESULTS: Overall, respondents preferred a blood test (79.6%) compared to a stool test (20.4%). However, increasing health system interactions had a strong impact on the likelihood of participating in either sampling method (p<0.001). Moreover, likelihood of participating in each of the four blood-screening scenarios was significantly lower than the current at-home stool sampling approach (all p<0.001). CONCLUSIONS: Blood-based screening methods require increased contact with the health system but these interactions have negative impact on screening likelihood. All blood-based scenarios showed lower screening likelihood ratings than the current at-home FIT approach. Thus, blood-based screening may not resolve suboptimal screening participation rates in Australia.

Screening technologies of pharmaceutical cocrystals:research advances / 国际药学研究杂志

Recently,the screening technologies of pharmaceutical cocrystals have become a research focus of improving drug solubility and stability. The technique changes medicine properties by intermolecular forces without changing the molecular structure , which provides new ways for the development of the insoluble drug. In addition,the formation of cocrystal gives new properties to drugs and intellectual property rights are effectively protected. This review focuses on screening technique ,which provides references for fur?ther studies of pharmaceutical cocrystal.

Screening technologies of pharmaceutical cocrystals: Research advances / 国际药学研究杂志

Recently, the screening technologies of pharmaceutical cocrystals have become a research focus of improving drug solubility and stability. The technique changes medicine properties by intermolecular forces without changing the molecular structure,which provides new ways for the development of the insoluble drug. In addition,the formation of cocrystal gives new properties to drugs and intellectual property rights are effectively protected. This review focuses on screening technique, which provides references for further studies of pharmaceutical cocrystal.