Stapled Phd Peptides Inhibit Doc Toxin Induced Growth Arrest in Salmonella.

Bacterial toxin inhibition is a promising approach to overcoming antibiotic failure. InSalmonella, knockout of the toxin Doc has been shown to significantly reduce the formation of antibiotic-tolerant persisters. Doc is a kinase that is inhibited in nontolerant cells by its cognate antitoxin, Phd. In this work, we have developed first-in-class stapled peptide antitoxin mimetics based on the Doc inhibitory sequence of Phd. After making a series of substitutions to improve bacterial uptake, we identified a lead stapled Phd peptide that is able to counteract Doc toxicity in Salmonella. This provides an exciting starting point for the further development of therapeutic peptides capable of reducing antibiotic persistence in pathogenic bacteria.

Modulators of protein-protein interactions as antimicrobial agents.

Protein-Protein interactions (PPIs) are involved in a myriad of cellular processes in all living organisms and the modulation of PPIs is already under investigation for the development of new drugs targeting cancers, autoimmune diseases and viruses. PPIs are also involved in the regulation of vital functions in bacteria and, therefore, targeting bacterial PPIs offers an attractive strategy for the development of antibiotics with novel modes of action. The latter are urgently needed to tackle multidrug-resistant and multidrug-tolerant bacteria. In this review, we describe recent developments in the modulation of PPIs in pathogenic bacteria for antibiotic development, including advanced small molecule and peptide inhibitors acting on bacterial PPIs involved in division, replication and transcription, outer membrane protein biogenesis, with an additional focus on toxin-antitoxin systems as upcoming drug targets.

A randomized controlled trial of real versus sham acupuncture for basal thumb joint arthritis.

We report a single-blinded randomized controlled trial comparing acupuncture to sham (non-penetrating) needling for relief of symptoms of basal thumb joint arthritis. Seventy acupuncture naive patients with basal thumb joint arthritis were randomized to receive true acupuncture or sham needling with 35 patients in each arm. Blinded baseline and post-treatment assessments included visual analogue pain scores for different grips and movement. Function was assessed using the Nelson questionnaire. Both groups showed statistically and clinically significant improvements in pain at week one post-treatment compared with baseline, but there was no difference between the treatment groups. The pain relief was comparable with published data for some standard treatments. Acupuncture did not perform better than sham needling in this study, indicating that pain relief may have been achieved through non-specific mechanisms. Level of evidence: I.

Structure-Activity Relationship Studies of a Novel Class of Transmission Blocking Antimalarials Targeting Male Gametes.

Malaria is still a leading cause of mortality among children in the developing world, and despite the immense progress made in reducing the global burden, further efforts are needed if eradication is to be achieved. In this context, targeting transmission is widely recognized as a necessary intervention toward that goal. After carrying out a screen to discover new transmission-blocking agents, herein we report our medicinal chemistry efforts to study the potential of the most robust hit, DDD01035881, as a male-gamete targeted compound. We reveal key structural features for the activity of this series and identify analogues with greater potency and improved metabolic stability. We believe this study lays the groundwork for further development of this series as a transmission blocking agent.

A high throughput screen for next-generation leads targeting malaria parasite transmission.

Spread of parasite resistance to artemisinin threatens current frontline antimalarial therapies, highlighting the need for new drugs with alternative modes of action. Since only 0.2-1% of asexual parasites differentiate into sexual, transmission-competent forms, targeting this natural bottleneck provides a tangible route to interrupt disease transmission and mitigate resistance selection. Here we present a high-throughput screen of gametogenesis against a ~70,000 compound diversity library, identifying seventeen drug-like molecules that target transmission. Hit molecules possess varied activity profiles including male-specific, dual acting male-female and dual-asexual-sexual, with one promising N-((4-hydroxychroman-4-yl)methyl)-sulphonamide scaffold found to have sub-micromolar activity in vitro and in vivo efficacy. Development of leads with modes of action focussed on the sexual stages of malaria parasite development provide a previously unexplored base from which future therapeutics can be developed, capable of preventing parasite transmission through the population.

Interfacing native and non-native peptides: using Affimers to recognise α-helix mimicking foldamers.

Selection methods are used to identify Affimers that recognise α-helix mimicking N-alkylated aromatic oligoamides thus demonstrating foldamer and natural α-amino acid codes are compatible.

Probing Protein Surfaces: QSAR Analysis with Helix Mimetics.

α-Helix-mediated protein-protein interactions (PPIs) are important targets for small-molecule inhibition; however, generic approaches to inhibitor design are in their infancy and would benefit from QSAR analyses to rationalise the noncovalent basis of molecular recognition by designed ligands. Using a helix mimetic based on an oligoamide scaffold, we have exploited the power of a modular synthesis to access compounds that can readily be used to understand the noncovalent determinants of hDM2 recognition by this series of cell-active p53/hDM2 inhibitors.

Selective and potent proteomimetic inhibitors of intracellular protein-protein interactions.

Inhibition of protein-protein interactions (PPIs) represents a major challenge in chemical biology and drug discovery. α-Helix mediated PPIs may be amenable to modulation using generic chemotypes, termed "proteomimetics", which can be assembled in a modular manner to reproduce the vectoral presentation of key side chains found on a helical motif from one partner within the PPI. In this work, it is demonstrated that by using a library of N-alkylated aromatic oligoamide helix mimetics, potent helix mimetics which reproduce their biophysical binding selectivity in a cellular context can be identified.

Multivalent helix mimetics for PPI-inhibition.

The exploitation of multivalent ligands for the inhibition of protein-protein interactions has not yet been explored as a supramolecular design strategy. This is despite the fact that protein-protein interactions typically occur within the context of multi-protein complexes and frequently exploit avidity effects or co-operative binding interactions to achieve high affinity interactions. In this paper we describe preliminary studies on the use of a multivalent N-alkylated aromatic oligoamide helix mimetic for inhibition of p53/hDM2 and establish that protein dimerisation is promoted, rather than enhanced binding resulting from a higher effective concentration of the ligand.

Orthogonal functionalisation of α-helix mimetics.

α-Helix mediated protein-protein interactions are of major therapeutic importance. As such, the design of inhibitors of this class of interaction is of significant interest. We present methodology to modify N-alkylated aromatic oligoamide α-helix mimetics using 'click' chemistry. The effect is shown to modulate the binding properties of a series of selective p53/hDM2 inhibitors.

Polyglycerol-based amphiphilic dendrons as potential siRNA carriers for in vivo applications.

The development of nonviral synthetic vectors for clinical application of gene therapy using siRNA transfection technology is of particular importance for treatment of human diseases, which is yet an unsolved challenge. By employing a rational design approach, we have synthesized a set of well-defined, low-molecular-weight dendritic polyglycerol-based amphiphiles, which are decorated peripherally with the DAPMA (N,N-di-(3-aminopropyl)-N-(methyl)amine) moiety. The main differences that were introduced in the structural motif relate to dendron generation and the type of linker between the hydrophilic and hydrophobic segment. The synthesized amphiphiles were then characterized for their aggregation behaviour and further evaluated with respect to their siRNA transfection potential by comparing their physico-chemical and biological features. Our findings demonstrated that all four synthesized amphiphiles yielded high gene binding affinities. Furthermore, the ester-linked compounds (G1-Ester-DAPMA, G2-Ester-DAPMA) revealed noticeable gene silencing in vitro without affecting the cell viability in the tumor cell line 786-O. Remarkably, neither G1-Ester-DAPMA nor G2-Ester-DAPMA induced inflammatory side effects after systemic administration in vivo, which is noteworthy because such highly positively charged compounds are typically associated with toxicity concerns which in turn supports their prospective application for in vivo purposes. Therefore, we believe that these structures may serve as new promising alternatives for nonviral siRNA delivery systems and have great potential for further synthetic modifications.