Publications

Deuterium, the heavy isotope of hydrogen, has unfolded as a cornerstone in modern drug discovery due to its potential to influence metabolic stability and pharmacokinetic behavior. The deuterium kinetic isotope effect (KIE), which strengthens carbon-deuterium bonds, make it possible to improve therapeutic efficacy while maintaining pharmacological activity. Although some deuterated drugs, notably donafenib and deutetrabenazine, have demonstrated clinically significant efficacy, their limited use is an effect of ongoing challenges with metabolic switching and species-specific variation, as well as inadequate mechanistic understanding. This review presents a systematic discussion of the recent innovations in site-selective deuteration, the principles that underpin the KIE process, and the effects of deuterium substitution on drug metabolism, toxicity, and blood-brain barrier penetration. It illustrates novel implications in oncology, rare diseases, and central nervous system disorders, as well as the integration of deuterated chemistry with modalities such as proteolysis-targeting chimaeras, peptides, and nucleic acid therapeutics. Furthermore, the review's discussion includes the current challenges, synthesis, analytical limits, and regulatory considerations that influence further development. Overall, the review offers a strategic roadmap for utilizing deuterium-enabled molecular engineering to accelerate the development of next-generation precision medicine, guiding rational design, innovation toward safer, longer-lasting, and more effective treatments.

JTD Keywords: Deucravacitinib, Deuterated drugs, Deuteration, Deuterium, Deutetrabenazine, Double-blind, Drug metabolism, Internal standard, Isotope, Labeled compounds, Mass-spectrometry, Medicinal chemistry, Metabolism, Pharmacokinetic properties, Site

Electron transfer (ET) between redox proteins is an essential process in the respiratory and photosynthetic transport chains. While intra-protein ET is well characterized, the experimental methods to investigate inter-protein ET are limited by the presence of the solvent and by the transient nature of the protein-protein interaction and ET event, which are averaged in protein ensembles. Wiring precisely oriented redox protein partners to the nanoscale electrodes of an electrochemical scanning tunneling microscope allows recording the time- and distance-dependence of the current flowing between them. These methods have revealed that the current flowing between individual protein pairs extends beyond tunneling distances and that it is electrochemically gated. However, the corresponding mechanism and the identity of the charge carriers in aqueous solution remain to be elucidated. To determine the species involved in long-distance charge transport between the redox partner proteins Cc and Cc 1 of the respiratory chain, recordings are performed as a function of pH, in heavy water solutions, and in degassed solutions. It is observed that the spatial span and electrochemical gating of long-distance currents are reduced at high pH, in heavy water, and at low oxygen concentration, showing that the currents are assisted by superoxide anions and by protons.

JTD Keywords: Catalysis, Coupled electron-transfer, Dynamics, Electrochemical stm, Gouy-chapman conduit, Grotthuss (grothuss) proton hopping conduction, Interface, Kinetic isotope effect kie, Mechanism, Mitochondria, Pathways, Ph, Proteins, Proton coupled electron transfer pcet, Reactive oxygen species ros, Reductase, Superoxide radical anion sox, Tyrosine phosphorylation

Bladder cancer treatment via intravesical drug administration achieves reasonable survival rates but suffers from low therapeutic efficacy. To address the latter, self-propelled nanoparticles or nanobots have been proposed, taking advantage of their enhanced diffusion and mixing capabilities in urine when compared with conventional drugs or passive nanoparticles. However, the translational capabilities of nanobots in treating bladder cancer are underexplored. Here, we tested radiolabelled mesoporous silica-based urease-powered nanobots in an orthotopic mouse model of bladder cancer. In vivo and ex vivo results demonstrated enhanced nanobot accumulation at the tumour site, with an eightfold increase revealed by positron emission tomography in vivo. Label-free optical contrast based on polarization-dependent scattered light-sheet microscopy of cleared bladders confirmed tumour penetration by nanobots ex vivo. Treating tumour-bearing mice with intravesically administered radio-iodinated nanobots for radionuclide therapy resulted in a tumour size reduction of about 90%, positioning nanobots as efficient delivery nanosystems for bladder cancer therapy.© 2024. The Author(s).

JTD Keywords: cell, drug-delivery, nanomotors, tissue, Bladder cancers, Cancer therapy, Diseases, Drug administration, Drug delivery, Enhanced diffusion, Enhanced mixing, Ex-vivo, In-vivo, Mammals, Nanobots, Nanoparticles, Nanosystems, Oncology, Positron emission tomography, Radioisotopes, Silica, Survival rate, Therapeutic efficacy, Tumor penetration, Tumors

Carbon-13 hyperpolarized pyruvate is about to become the next-generation contrast agent for molecular magnetic resonance imaging of cancer and other diseases. Here, efficient and rapid pyruvate hyperpolarization is achieved via signal amplification by reversible exchange (SABRE) with parahydrogen through synergistic use of substrate deuteration, alternating, and static microtesla magnetic fields. Up to 22 and 6% long-lasting 13C polarization (T1 = 3.7 ± 0.25 and 1.7 ± 0.1 min) is demonstrated for the C1 and C2 nuclear sites, respectively. The remarkable polarization levels become possible as a result of favorable relaxation dynamics at the microtesla fields. The ultralong polarization lifetimes will be conducive to yielding high polarization after purification, quality assurance, and injection of the hyperpolarized molecular imaging probes. These results pave the way to future in vivo translation of carbon-13 hyperpolarized molecular imaging probes prepared by this approach.

JTD Keywords: hydrogen, nmr, Carbon isotopes, Carbon-13, Magnetic resonance imaging, Magnetic resonance spectroscopy, Pyruvic acid, Sabre