Peptide Therapeutics and the Pharmaceutical Industry: Barriers Encountered Translating from the Laboratory to Patients

Peptides are receiving increasing interest as clinical therapeutics. These highly tunable molecules can be tailored to biocompatibility and biodegradability with simultaneously selective and potent therapeutic effects. Despite challenges regarding up-scaling and licensing of peptide products, their vast clinical potential is reflected in the 60 plus peptide-based therapeutics already on the market, and the further 500 derivatives currently in developmental stages. Peptides are proving effective for a multitude of disease states including: type 2 diabetes (controlled using the licensed glucagon-like peptide-1 receptor liraglutide); irritable bowel syndrome managed with linaclotide (currently at approval stages); acromegaly (treated with octapeptide somostatin analogues lanreotide and octreotide); selective or broad spectrum microbicidal agents such as the Gram-positive selective PTP-7 and antifungal heliomicin; anticancer agents including goserelin used as either adjuvant or for prostate and breast cancer,and the first marketed peptide derived vaccine against prostate cancer, sipuleucel-T. Research is also focusing on improving the biostability of peptides. This is achieved through a number of mechanisms ranging from replacement of naturally occurring L-amino acid enantiomers with D-amino acid forms, lipidation, peptidomimetics, N-methylation, cyclization and exploitation of carrier systems. The development of self-assembling peptides are paving the way for sustained release peptide formulations and already two such licensed examples exist, lanreotide and octreotide. The versatility and tunability of peptide-based products is resulting in increased translation of peptide therapies, however significant challenges remain with regard to their wider implementation. This review highlights some of the notable peptide therapeutics discovered to date and the difficulties encountered by the pharmaceutica lindustry in translating these molecules to the clinical setting for patient benefit, providing some possible solutions to the most challenging barriers. 

Climate change and the long-term viability of the World’s busiest heavy haul ice road

Climate models project that the northern high latitudes will warm at a rate in excess of the global mean. This will pose severe problems for Arctic and sub-Arctic infrastructure dependent on maintaining low temperatures for structural integrity. This is the case for the economically important Tibbitt to Contwoyto Winter Road (TCWR)—the world’s busiest heavy haul ice road, spanning 400 km across mostly frozen lakes within the Northwest Territories of Canada. In this study, future climate scenarios are developed for the region using statistical downscaling methods. In addition, changes in lake ice thickness are projected based on historical relationships between measured ice thickness and air temperatures. These projections are used to infer the theoretical operational dates of the TCWR based on weight limits for trucks on the ice. Results across three climate models driven by four RCPs reveal a considerable warming trend over the coming decades. Projected changes in ice thickness reveal a trend towards thinner lake ice and a reduced time window when lake ice is at sufficient thickness to support trucks on the ice road, driven by increasing future temperatures. Given the uncertainties inherent in climate modelling and the resultant projections, caution should be exercised in interpreting the magnitude of these scenarios. More certain is the direction of change, with a clear trend towards winter warming that will reduce the operation time window of the TCWR. This illustrates the need for planners and policymakers to consider future changes in climate when planning annual haulage along the TCWR.

Identification and bioactivity evaluation of two novel temporins from the skin secretion of the European edible frog, Pelophylax kl. Esculentus

The amphibian temporins, amongst the smallest antimicrobial peptides (AMPs), are α-helical, amphipathic, hydrophobic and cationic and are active mainly against Gram-positive bacteria but inactive or weakly active against Gram-negative bacteria. Here, we report two novel members of the temporin family, named temporin-1Ee (FLPVIAGVLSKLFamide) and temporin-1Re (FLPGLLAGLLamide), whose biosynthetic precursor structures were deduced from clones obtained from skin secretion-derived cDNA libraries of the European edible frog, Pelophylax kl. esculentus, by ‘shotgun’ cloning. Deduction of the molecular masses of each mature processed peptide from respective cloned cDNAs was used to locate respective molecules in reverse-phase HPLC fractions of secretion. Temporin-1Ee (MIC = 10 μM) and temporin-1Re (MIC = 60 μM) were both found to be active against Gram-positive Staphylococcus aureus, but retaining a weak haemolytic activity. To our knowledge, Single-site substitutions can dramatically change the spectrum of activity of a given temporin. Compared with temporine-1Ec, just one chemically-conservative substitution (Val8 instead of Leu8), temporin-1Ee bearing a net charge of +2 displays broad-spectrum activity with particularly high potency on the clinically relevant Gram-negative strains, Escherichia coli (MIC = 40 μM). These factors bode well for translating temporins to be potential drug candidates for the design of new and valuable anti-infective agents.

National climate policies across Europe and their impacts on cities strategies

Globally, efforts are underway to reduce anthropogenic greenhouse gas emissions and to adapt to climate change impacts at the local level. However, there is a poor understanding of the relationship between city strategies on climate change mitigation and adaptation and the relevant policies at national and European level. This paper describes a comparative study and evaluation of cross-national policy. It reports the findings of studying the climate change strategies or plans from 200 European cities from Austria, Belgium, Estonia, Finland, France, Germany, Ireland, Italy, Netherlands, Spain and the United Kingdom. The study highlights the shared responsibility of global, European, national, regional and city policies. An interpretation and illustration of the influences from international and national networks and policy makers in stimulating the development of local strategies and actions is proposed. It was found that there is no archetypical way of planning for climate change, and multiple interests and motivations are inevitable. Our research warrants the need for a multi-scale approach to climate policy in the future, mainly ensuring sufficient capacity and resource to enable local authorities to plan and respond to their specific climate change agenda for maximising the management potentials for translating environmental challenges into opportunities.

The role of Lean at the interface with between operations management and applied services within a large aerospace organisation: a boundary spanning perspective

Increased complexity in large design and manufacturing organisations requires improvements at the operations management (OM)–applied service (AS) interface areas to improve project effectiveness. The aim of this paper is explore the role of Lean in improving the longitudinal efficiency of the OM–AS interface within a large aerospace organisation using Lean principles and boundary spanning theory. The methodology was an exploratory longitudinal case approach including exploratory interviews (n = 21), focus groups (n = 2), facilitated action-research workshops (n = 2) and two trials or experiments using longitudinal data involving both OM and AS personnel working at the interface. The findings draw upon Lean principles and boundary spanning theory to guide and interpret the findings. It was found that misinterpretation, and forced implementation, of OM-based Lean terminology and practice in the OM–AS interface space led to delays and misplaced resources. Rather both OM and AS staff were challenged to develop a cross boundary understanding of Lean-based boundary (knowledge) objects in interpreting OM requests. The longitudinal findings from the experiments showed that the development of Lean Performance measurements and lean Value Stream constructs was more successful when these Lean constructs were treated as boundary (knowledge) objects requiring transformation over time to orchestrate improved effectiveness and in leading to consistent terminology and understanding between the OM–AS boundary spanning team.