12 research outputs found
Successful use of axonal transport for drug delivery by synthetic molecular vehicles
We report the use of axonal transport to achieve intraneural drug delivery. We constructed a novel tripartite complex of an axonal transport facilitator conjugated to a linker molecule bearing up to a hundred reversibly attached drug molecules. The complex efficiently enters nerve terminals after intramuscular or intradermal administration and travels within axonal processes to neuron cell bodies. The tripartite agent provided 100-fold amplification of saturable neural uptake events, delivering multiple drug molecules per complex. _In vivo_, analgesic drug delivery to systemic and to non-targeted neural tissues was greatly reduced compared to existing routes of administration, thus exemplifying the possibility of specific nerve root targeting and effectively increasing the potency of the candidate drug gabapentin 300-fold relative to oral administration
Tri-partite complex for axonal transport drug delivery achieves pharmacological effect.
BACKGROUND: Targeted delivery of pharmaceutical agents into selected populations of CNS (Central Nervous System) neurons is an extremely compelling goal. Currently, systemic methods are generally used for delivery of pain medications, anti-virals for treatment of dermatomal infections, anti-spasmodics, and neuroprotectants. Systemic side effects or undesirable effects on parts of the CNS that are not involved in the pathology limit efficacy and limit clinical utility for many classes of pharmaceuticals. Axonal transport from the periphery offers a possible selective route, but there has been little progress towards design of agents that can accomplish targeted delivery via this intraneural route. To achieve this goal, we developed a tripartite molecular construction concept involving an axonal transport facilitator molecule, a polymer linker, and a large number of drug molecules conjugated to the linker, then sought to evaluate its neurobiology and pharmacological behavior. RESULTS: We developed chemical synthesis methodologies for assembling these tripartite complexes using a variety of axonal transport facilitators including nerve growth factor, wheat germ agglutinin, and synthetic facilitators derived from phage display work. Loading of up to 100 drug molecules per complex was achieved. Conjugation methods were used that allowed the drugs to be released in active form inside the cell body after transport. Intramuscular and intradermal injection proved effective for introducing pharmacologically effective doses into selected populations of CNS neurons. Pharmacological efficacy with gabapentin in a paw withdrawal latency model revealed a ten fold increase in half life and a 300 fold decrease in necessary dose relative to systemic administration for gabapentin when the drug was delivered by axonal transport using the tripartite vehicle. CONCLUSION: Specific targeting of selected subpopulations of CNS neurons for drug delivery by axonal transport holds great promise. The data shown here provide a basic framework for the intraneural pharmacology of this tripartite complex. The pharmacologically efficacious drug delivery demonstrated here verify the fundamental feasibility of using axonal transport for targeted drug delivery.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are
Potential therapeutic targets from Mycobacterium abscessus (Mab): recently reported efforts towards the discovery of novel antibacterial agents to treat Mab infections.
Mycobacterium abscessus (Mab) are rapidly growing mycobacteria that cause severe and persistent infections in both skin and lung tissues. Treatment regimens involve the extended usage of complex combinations of drugs, often leading to severe adverse side effects, particularly in immunocompromised patients. Current macrolide therapies are gradually proving to be less effective, largely due to emergence of antibiotic resistance; there is therefore an increasing need for the discovery of new antibacterials that are active against Mab. This review highlights recent research centred upon a number of potential therapeutic targets from Mab (Ag85C, ClpC1, GyrB, MmpL3 and TrmD), and discusses the various approaches used to discover small molecule inhibitors, in the search for future antibiotics for the treatment of Mab infections
A new strategy for hit generation: Novel in cellulo active inhibitors of CYP121A1 from Mycobacterium tuberculosis via a combined X-ray crystallographic and phenotypic screening approach (XP screen)
There is a pressing need for new drugs against tuberculosis (TB) to combat the growing resistance
to current antituberculars. Herein a novel strategy is described for hit generation against promising
TB targets involving X-ray crystallographic screening in combination with phenotypic screening.
This combined approach (XP Screen) affords both a validation of target engagement as well as
determination of in cellulo activity. The utility of this method is illustrated by way of an XP Screen
against CYP121A1, a cytochrome P450 enzyme from Mycobacterium tuberculosis (Mtb)
championed as a validated drug discovery target. A focused screening set was synthesized and
tested by such means, with several members of the set showing promising activity against Mtb
strain H37Rv. One compound was observed as an X-ray hit against CYP121A1 and showed
improved activity against Mtb strain H37Rv under multiple assay conditions (pan-assay activity).
Data obtained during X-ray crystallographic screening were utilized in a structure-based campaign
to design a limited number of analogues (less than twenty), many of which also showed pan-assay
activity against Mtb strain H37Rv. These included the benzo[b][1,4]oxazine derivative (MIC90 6.25
µM), a novel hit compound suitable as a starting point for a more involved lead-to-clinical candidate
medicinal chemistry campaign
Discovery of a Potent Nonpeptidomimetic, Small-Molecule Antagonist of Cellular Inhibitor of Apoptosis Protein 1 (cIAP1) and X‑Linked Inhibitor of Apoptosis Protein (XIAP)
XIAP and cIAP1 are
members of the inhibitor of apoptosis protein
(IAP) family and are key regulators of anti-apoptotic and pro-survival
signaling pathways. Overexpression of IAPs occurs in various cancers
and has been associated with tumor progression and resistance to treatment.
Structure-based drug design (SBDD) guided by structural information
from X-ray crystallography, computational studies, and NMR solution
conformational analysis was successfully applied to a fragment-derived
lead resulting in AT-IAP, a potent, orally bioavailable, dual antagonist
of XIAP and cIAP1 and a structurally novel chemical probe for IAP
biology
Fragment-Based Discovery of Type I Inhibitors of Maternal Embryonic Leucine Zipper Kinase
Fragment-based
drug design was successfully applied to maternal embryonic leucine
zipper kinase (MELK). A low affinity (160 μM) fragment hit was
identified, which bound to the hinge region with an atypical binding
mode, and this was optimized using structure-based design into a low-nanomolar
and cell-penetrant inhibitor, with a good selectivity profile, suitable
for use as a chemical probe for elucidation of MELK biology