The quest for down scale representativeness: how to exploit CFD to design a shear study for vaccines.

In this work, we exploit computational fluid dynamics (CFD) to evaluate stirred tank reactor (STR) process engineer parameters (PEP) and design a scale-down system (SDS) to be representative of the formulation and filling process steps for an Aluminum adjuvanted vaccine drug product (DP). To study the shear history in the SDS we used the concept of , combined with an appropriate stirring speed down scale strategy comprising of either (i) tip speed equivalence, widely used as a scale-up criterion for a shear-sensitive product, or (ii) rotating shear, a shear metric introduced by Metz and Otto in 1957 but never used as scaling criterion. The outcome of the CFD simulations shows that the tip equivalence generates a worst-case SDS in terms of shear, whereas the rotating shear scaling approach could be used to design a more representative SDS.

CMC Strategies and Advanced Technologies for Vaccine Development to Boost Acceleration and Pandemic Preparedness.

This review reports on an overview of key enablers of acceleration/pandemic and preparedness, covering CMC strategies as well as technical innovations in vaccine development. Considerations are shared on implementation hurdles and opportunities to drive sustained acceleration for vaccine development and considers learnings from the COVID pandemic and direct experience in addressing unmet medical needs. These reflections focus on (i) the importance of a cross-disciplinary framework of technical expectations ranging from target antigen identification to launch and life-cycle management; (ii) the use of prior platform knowledge across similar or products/vaccine types; (iii) the implementation of innovation and digital tools for fast development and innovative control strategies.

Clinically proven specification setting for a meningococcal serogroup a conjugate vaccine.

GSK is currently working to improve the commercial presentation of the licensed quadrivalent conjugate vaccine (Menveo) for use against meningococcal serogroup A, C, W, Y (MenACWY) infections. Menveo consists of a primary, lyophilized vial, containing the serogroup A antigen that is reconstituted with the content of a second, liquid, vial that contains the serogroup C, W, Y antigens, to give the final liquid MenACWY product. Since the MenA structure is prone to hydrolytic degradation in liquid formulations, we used mathematical models to rationally design a clinical Phase 2 development plan and provide end of shelf-life (EoSL) and release specification setting for the MenACWY liquid product.

Correction to "NMR Assays for Estimating the -Acetyl Content of Meningococcal Polysaccharide Serogroup A in Quadrivalent Conjugate Vaccine Formulation".

[This corrects the article DOI: 10.1021/acsomega.9b01678.

NMR Assays for Estimating the -Acetyl Content of Meningococcal Polysaccharide Serogroup A in Quadrivalent Conjugate Vaccine Formulation.

The use of multivalent glycoconjugate vaccines has dramatically contributed to reduce the incidence of meningococcal infectious disease. The advanced structural characterization of polysaccharide conjugates leads to enhancements in the quality and control of the products. Here, we report a novel nuclear magnetic resonance (NMR) method to confirm the identity and structural conformity (e.

Challenging clinically unresponsive medullary thyroid cancer: Discovery and pharmacological activity of novel RET inhibitors.

It is now known that "gain of function" mutations of RET (REarranged during Transfection) kinase are specific and key oncogenic events in the onset of thyroid gland cancers such as the Medullary Thyroid Carcinoma (MTC). Although a number of RET inhibitors exist and are capable of inhibiting RET variants, in which mutations are outside the enzyme active site, the majority becomes dramatically ineffective when mutations are within the protein active site (V804L and V804M). Pursuing a receptor-based virtual screening against the kinase domain of RET, we found that compound 5 is able to inhibit efficiently both wild type and V804L mutant RET.

Targeting the minor pocket of C5aR for the rational design of an oral allosteric inhibitor for inflammatory and neuropathic pain relief.

Chronic pain resulting from inflammatory and neuropathic disorders causes considerable economic and social burden. Pharmacological therapies currently available for certain types of pain are only partially effective and may cause severe adverse side effects. The C5a anaphylatoxin acting on its cognate G protein-coupled receptor (GPCR), C5aR, is a potent pronociceptive mediator in several models of inflammatory and neuropathic pain.

QSAR modeling and data mining link Torsades de Pointes risk to the interplay of extent of metabolism, active transport, and HERG liability.

We collected 1173 hERG patch clamp (PC) data (IC50) from the literature to derive twelve classification models for hERG inhibition, covering a large variety of chemical descriptors and classification algorithms. Models were generated using 545 molecules and validated through 258 external molecules tested in PC experiments. We also evaluated the suitability of the best models to predict the activity of 26 proprietary compounds tested in radioligand binding displacement (RBD).

Aryltriflates as a Neglected Moiety in Medicinal Chemistry: A Case Study from a Lead Optimization of CXCL8 Inhibitors.

Interleukin-8 and growth related oncogene-α-chemokines (formerly CXCL8 and CXCL1, respectively) mediate chemotaxis of neutrophils to inflammatory sites via interactions with two transmembrane receptors, the type A CXCL8 receptor (CXCR1) and the type B CXCL8 receptor (CXCR2). In a previous work, we published the molecular modeling-driven structure activity relationship (SAR) results culminated in the discovery of R-(-)-2-[(4'-trifluoromethanesulphonyloxy)phenyl]-N-methanesulfonyl propionamide (19), in which an unusual aryltriflate moiety was embedded. Although triflates are broadly used in organic synthesis, this group is scarcely used in medicinal chemistry programs.

Exploring the activation mechanism of TRPM8 channel by targeted MD simulations.

The TRPM8 cation channel belongs to the superfamily of transient receptor potential (TRP) channels. It is involved in non-painful cool sensation and triggered by diverse chemical and physical stimuli whose precise activation mechanism is still unknown. The study presents a set of targeted molecular dynamics (MD) simulations involving selected complexes of the TRPM8 channel whose homology model was recently generated by some of us.

GPR55: Current knowledge and future perspectives of a purported "Type-3" cannabinoid receptor.

In the last decade, accumulated evidence highlighted that GPR55 might be activated by several classical cannabinoid ligands, making this orphan receptor the main candidate to be considered as the "third" cannabinoid receptor. The investigation of its pharmacology has often provided divergent and more intricate results that have complicated the understanding of the physiological role of GPR55. Nevertheless, the patent analysis regarding GPR55 outlines the fair interest of big pharmaceutical companies, especially in the first years of this decade.

Structure-Activity Relationship of novel phenylacetic CXCR1 inhibitors.

We reported recently the Structure-Activity Relationship (SAR) of a class of CXCL8 allosteric modulators. They invariably share a 2-arylpropionic moiety so far considered a key structural determinant of the biological activity. We show the results of recent SAR studies on a novel series of phenylacetic derivatives supported by a combined approach of mutagenesis experiments and conformational analysis.

Design of noncompetitive interleukin-8 inhibitors acting on CXCR1 and CXCR2.

Chemokines CXCL8 and CXCL1 play a key role in the recruitment of neutrophils at the site of inflammation. CXCL8 binds two membrane receptors, CXCR1 and CXCR2, whereas CXCL1 is a selective agonist for CXCR2. In the past decade, the physiopathological role of CXCL8 and CXCL1 has been investigated.

Predicting human serum albumin affinity of interleukin-8 (CXCL8) inhibitors by 3D-QSPR approach.

A novel class of 2-(R)-phenylpropionamides has been recently reported to inhibit in vitro and in vivo interleukin-8 (CXCL8)-induced biological activities. These CXCL8 inhibitors are derivatives of phenylpropionic nonsteroidal antiinflammatory drugs (NSAIDs), high-affinity ligands for site II of human serum albumin (HSA). Up to date, only a limited number of in silico models for the prediction of albumin protein binding are available.

Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2: prevention of reperfusion injury.

The chemokine CXC ligand 8 (CXCL8)/IL-8 and related agonists recruit and activate polymorphonuclear cells by binding the CXC chemokine receptor 1 (CXCR1) and CXCR2. Here we characterize the unique mode of action of a small-molecule inhibitor (Repertaxin) of CXCR1 and CXCR2. Structural and biochemical data are consistent with a noncompetitive allosteric mode of interaction between CXCR1 and Repertaxin, which, by locking CXCR1 in an inactive conformation, prevents signaling.