A New Vista of Aldehyde Dehydrogenase 1A3 (ALDH1A3): New Specific Inhibitors and Activity-Based Probes Targeting ALDH1A3 Dependent Pathways in Glioblastoma, Mesothelioma and Other Cancers.

Aldehyde dehydrogenases of the subfamily 1A (ALDH1A) are enzymes necessary for the oxidation of all-trans or 9-cis retinal to retinoic acid (RA). Retinoic acid and its derivatives are important for normal development and maintenance of epithelia, reproduction, memory, and immune function in adults. Moreover, in recent years, it has been demonstrated that ALDH1A members are also expressed and functional in several human cancers where their role is not limited to the synthesis of RA. Here, we review the current knowledge about ALDH1A3, one of the 1A isoforms, in cancers with an emphasis on two of the deadliest tumors that affect humans: glioblastoma multiforme and mesothelioma. In both tumors, ALDH1A3 is considered a negative prognostic factor, and its level correlates with excessive proliferation, chemoresistance, and invasiveness. We also review the recent attempts to develop both ALDH1A3-selective inhibitors for cancer therapy and ALDH1A3-specific fluorescent substrates for fluorescence-guided tumor resection.

An insight into the last 5-year patents on Porphyromonas gingivalis and Streptococcus mutans, the pivotal pathogens in the oral cavity.

INTRODUCTION: The oral cavity harbors an extensive array of over 700 microorganisms, forming the most complex biome of the entire human body, with bacterial species being the most abundant. Oral diseases, e.g. periodontitis and caries, are strictly associated with bacterial dysbiosis. Porphyromonas gingivalis and Streptococcus mutans stand out among bacteria colonizing the oral cavity. AREAS COVERED: After a brief overview of the bacterial populations in the oral cavity and their roles in regulating (flora) oral cavity or causing diseases like periodontal and cariogenic pathogens, we focused our attention on P. gingivalis and S. mutans, searching for the last-5-year patents dealing with the proposal of new strategies to fight their infections. Following the PRISMA protocol, we filtered the results and analyzed over 100 applied/granted patents, to provide an in-depth insight into this R&D scenario. EXPERT OPINION: Several antibacterial proposals have been patented in this period, from both chemical - peptides and small molecules - and biological - probiotics and antibodies - sources, along with natural extracts, polymers, and drug delivery systems. Most of the inventors are from China and Korea and their studies also investigated anti-inflammatory and antioxidant effects, being beneficial to oral health through a prophylactic, protective, or curative effect.

Identification of N-Acyl Hydrazones as New Non-Zinc-Binding MMP-13 Inhibitors by Structure-Based Virtual Screening Studies and Chemical Optimization.

Matrix metalloproteinase 13 plays a central role in osteoarthritis (OA), as its overexpression induces an excessive breakdown of collagen that results in an imbalance between collagen synthesis and degradation in the joint, leading to progressive articular cartilage degradation. Therefore, MMP-13 has been proposed as a key therapeutic target for OA. Here we have developed a virtual screening workflow aimed at identifying selective non-zinc-binding MMP-13 inhibitors by targeting the deep S1' pocket of MMP-13. Three ligands were found to inhibit MMP-13 in the µM range, and one of these showed selectivity over other MMPs. A structure-based analysis guided the chemical optimization of the hit compound, leading to the obtaining of a new N-acyl hydrazone-based derivative with improved inhibitory activity and selectivity for the target enzyme.