Pharmacology and Toxicology

eLife assessment

This compelling and novel mathematical method assesses drug pro-arrhythmic cardiotoxicity by examining the electrophysiology of untreated cardiac cells. It will be valuable for future drug safety design.

eLife assessment

In this manuscript, a method to test a large number of drug combinations in a single cell culture sample is presented. The strength of the evidence lies in their multiple experiments with different combinations of agents. The paper suggests that results from this application are feasible and the methodology could be applied in other laboratories to use drug combinations for defined outcomes.

eLife assessment

By combining electrophysiological analysis of mutant channels and molecular dynamics simulations, this important study identifies a common binding site for two structurally distinct activators of KCNQ1-KCNE1 channels. The findings represent an important advance for the field, with convincing functional and computational data to support the claims. The work will be of interest to those studying the binding of small molecule drugs to membrane protein complexes.

eLife assessment

This paper is of potential interest to scientists within the field of drug-induced liver injury. The concept of the study is interesting by generating mitochondrial genotype-specific liver cell lines to evaluate idiosyncratic hepatotoxicity. While the proof-of-concept is clearly presented, the current data do not yet allow to draw broad conclusions about the significance of the study in terms of drug effects.

eLife assessment

This fundamental study is important and carefully executed, providing important insights into the allosteric regulation of GPCRs with exceptional strength of evidence. This work will be of interest to a wide audience in drug discovery and receptor biology. The major strengths are the comprehensive structural and pharmacological characterization with only minor weaknesses, most notably a concern regarding the approach used to quantify efficacy.

eLife assessment

The authors have developed a useful model for how proteins that mediate a connection between invariant components of the T cell antigen receptor and leukaemic cells antigens, called bispecific engagers (BiTEs), mediate immunological synapse formation and impact T cell search for tumour cells in vivo. The model was compared against the in vitro experiments and in vivo data following a solid approach. The developed framework could provide a direction for employing computational mechanistic models for evaluating various strategies for BiTE treatments.

eLife assessment

This study presents the important finding of an unusual uncompetitive inhibitor (ECSI#6) of the serotonin transporter that removes the neurotransmitter serotonin from the synaptic cleft. Through careful and comprehensive analysis, the authors convincingly show that the molecule most likely binds to the inward-facing and K+-bound state and that it assists in folding and targeting the transporter. The work will be of interest to those engaged in biophysical analyses of the serotonin transporter, and colleagues developing pharmacological chaperoning strategies for transporters in general.

eLife assessment

This manuscript proposes that metformin protects against elevated intraocular pressure and oxidative injury by regulating cytoskeleton remodeling through the integrin/ROCK pathway, thus providing a new direction for further exploration toward the treatment of primary open-angle glaucoma as well as investigation of oxidative injury in multiple settings.

Evaluation Summary:

This paper will be of interest to the pharmacology community with interest in available drug treatments for osteoporosis and how to optimize these. The key findings of the paper are based on in silico results and indicate that combined drug treatments may be more efficient in treatment of osteoporosis. This could have a significant impact on clinical management of osteoporosis patients.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

The authors present a manuscript addressing an important unmet need, specifically focused on understanding the effects of high protein on hematopoiesis. This information can be of interest to basic biologists and clinicians who specialize in the areas of various diseases associated with elevated protein concentration (e.g. infections, inflammation, multiple myeloma, renal failure, etc). This is in part what makes for the complexity in studying this entity as the consequences of such disparate diseases are difficult to parcel out as causes of which specific disease manifestations. Furthermore, the presented work is done in an invertebrate model without additional confirmation in other model systems. Taken together, the work, which is plentiful in experiments, provides an incomplete understanding of cause and effect, leading to overinterpretation of results and overstating of derived conclusions.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

This article proposes methodology and accompanying software for robustly fitting dose-response curves where response is a number between 0 and 1. When response is transformed using the common logistic transformation, values close to 0 or 1 become large in magnitude, unduly influencing the fitted curve after back-transformation and introducing bias in the estimate of certain parameters. The proposed approach, called Robust and Efficient Assessment of Potency, is less perturbed by these extreme measurements.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

The authors describe a comprehensive characterization of a new humanized FSH blocking antibody (MS-Hu6), which they have studied in-depth in terms of its efficacy on bone and fat tissues. They provide compelling data on mouse and monkey species with a complete evaluation of its pharmacokinetics and biodistribution and characterize its effect for the treatment of obesity and bone loss. It is an important contribution and will be useful to a general readership in endocrinology, bone and fat metabolism.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

A challenge to understanding the physiology and therapeutic potential of G protein-coupled receptors (GPCRs) is to understand the range of their couplings to different G proteins. Avet et al developed of a novel set of biosensors to assess the coupling specificity of 100 therapeutically relevant G protein-coupled receptors (GPCRs) to various G protein isoforms and arrestins. The novel screen and results obtained with reference ligands will have broad use for researchers studying GPCRs, potentially impacting discovery of new physiological pathways, understanding adverse effects of currently marketed therapeutics, and discovery of novel, safer therapeutics.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

This study is a meta-analysis of previously reported studies on G protein-coupled receptor (GPCR) coupling to G proteins. Three separate data sets that describe the coupling of members of the superfamily of non-sensory GPCRs (~200 genes) to the large family of G protein alpha subunits (~20 genes). The authors try to arrive at a consensus for receptor-G protein coupling from the three data sets, as well as identify and highlight differences or incongruencies. Compiling these vast data sets into a unified format will be extremely useful for investigators to understand receptor and effector relationships. The meta-analysis will help to deconvolute the complex physiology and pharmacology underlying hormone or drug actions acting on receptor superfamilies.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

This exciting study reports on the characterization of a novel compound that preferentially targets Nav1.6 voltage-gated sodium channels and shows substantial activity against epilepsy associated SCN8A mutations and seizure activity in a variety of animal models. This compound and approach has significant promise to be translated into a therapeutic for individuals with treatment resistant epilepsy.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

Nichols et al. developed and characterized the first fluorescent sensors for several nicotinic receptor partial agonists relevant to smoking cessation. It is potentially a major advance for the field. They leveraged crystallography to understand the mechanism by which the ligands enhance fluorescence, then characterized top sensors for sensitivity, selectivity, and kinetics, and their utility in plasma membrane and ER sensing in neurons and cell lines. The tools developed by this team will enable investigators to track nicotinic receptor partial agonists in different subcellular compartments with relatively fast time resolution.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1, Reviewer #2 and Reviewer #3 agreed to share their names with the authors.)

Evaluation Summary:

This paper will be of interest to oncologists and dermatologists and has high clinical relevance. It reveals a novel mechanism of EGFR inhibitor-induced rash which be may closely related to atrophy of dermal white adipose tissue (dWAT). A series of experimental manipulations dissect the mechanism with a murine model, supporting the major claims of the paper.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

Low voltage-activated T-type calcium channels (CaV3.1-3.3) are important for several physiological processes. It is challenging to distinguish their specific physiological / pathophysiological roles as they share similar biophysical properties, expression profiles and there is a lack of subtype selective pharmacology. This study reports a spider toxin, Pn3a, which exhibits 100-fold selectivity for inhibiting CaV3.3 over CaV3.1 and CaV3.2 isoforms, and which therefore makes for an excellent reagent for the physiological study of CaV3.3.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

This work reveals the pathway by which an important human parasite synthesizes a nuclear hormone receptor ligand critical for progression through its life cycle and demonstrates the potential therapeutic implications of perturbing this pathway. The experiments are insightfully and expertly conceived, designed and executed, and the data support the conclusions. This manuscript will be of general interest to parasitologists, nematode biologists, and those studying transcriptional regulatory networks governed by ligand-gated nuclear receptors.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)

Evaluation Summary:

This paper is of interest to a broad audience of cell biologists, pharmacologists and researchers who work in metabolic diseases. The work provides substantial new insights into the mechanism of action for a plant derived pentacyclic triterpene called celastrol elastrol, in effectively reducing the high fat diet induced tissue hypertrophy in mouse liver and adipose. A series of compelling experiments depict the site of covalent inhibition of the ER stress sensor GRP78 as essential for the beneficial effects in-vivo, supporting the main conclusions.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)