Current Drug Targets - Current Issue

Biofilms are complicated microbial communities attached to surfaces, bringing about serious clinical, industrial, and environmental issues due to their resistance to conventional antimicrobial treatments. One critical factor of biofilm formation and persistence is quorum sensing - a mechanism that enables cell-to-cell communication and controls the gene expression pattern depending on the population density. It is based on the constant production, secretion, and response of small signalling molecules, termed auto-inducers. The main role of QS is the regulation of vital processes in the cell, such as biofilm formation and virulence factor production, which intensify pathogenicity, drug resistance, and toxin production. In this respect, interruption of QS can be a potential druggable target, and the discovery of QS-inhibiting agents as anti-virulence compounds may offer an alternative therapeutic approach to conventional antibiotics. Quorum sensing inhibition implies a novel strategy against microbial pathogenicity as it only reduces cell-to-cell communication pathways and thus attenuates various physiological responses coordinated by the QS mechanism. Hence, it qualifies as a suitable target for drug discovery. This article provides a comprehensive overview of the Las, Rhl, Pqs, and Iqs quorum sensing cascades in Pseudomonas aeruginosa, elucidating their molecular targets and regulatory roles in virulence. Focusing on therapeutic potential, the review highlights recently identified QS inhibitors and their mechanisms of action, focusing on molecular targets within QS cascades. The review underscores the critical importance of identifying key molecular targets within QS cascades, as their precise knowledge enables the strategic design of inhibitors that disrupt bacterial communication. This work advances innovative therapeutic paradigms by identifying key QS targets, offering promising strategies to disrupt virulence pathways and combat P. aeruginosa infections.

Malaria control is severely hindered by a lack of effective treatment options and the rise of drug-resistant strains of the parasite. Despite the absence of a reliable vaccine, the therapeutic application of antimalarial drugs remains the primary strategy for controlling and preventing malaria. However, most existing antimalarial drugs target the blood stage of the parasite's lifecycle and may not effectively eliminate liver-stage parasites, limiting their efficacy in complete parasite clearance. The urgent need for novel antimalarial drugs with innovative mechanisms of action is critical to preventing a major public health crisis. Developing new antimalarial drugs involves both optimizing existing compounds and designing novel molecules that target unique biological pathways in Plasmodium. This review explores promising drug targets, including heme detoxification, food vacuole function, mitochondria, protein kinases, apicoplast pathways, nucleic acid biosynthesis, fatty acid metabolism, the electron transport chain (ETC), and P-Type ATPases. Lead candidates targeting these mechanisms are discussed, highlighting their potential as next-generation antimalarial agents. Additionally, we provide updates on clinically validated targets and the progress of antimalarial drug candidates in different stages of clinical development. Emerging therapeutic strategies focusing on malarial transporters, protein interaction networks, and substrate repertoires offer new avenues for drug discovery. A deeper understanding of these pathways can enhance drug efficacy, mitigate resistance, and support the development of long-lasting antimalarial therapies. This review aims to provide insights into the current landscape of antimalarial drug development and future directions for combating malaria.

Recent studies have identified significant advancements in understanding the role of PEST sequence-containing proteins in retinal neovascularization. Retinal neovascularization, a critical pathological process, leads to severe visual impairment associated with conditions such as diabetic retinopathy, retinopathy of prematurity, and neovascular age-related macular degeneration. These conditions represent the leading causes of blindness worldwide. Although initially effective, current anti-VEGF treatments can lose efficacy over time and impose a burden due to frequent administrations, highlighting the need for novel therapeutic targets. PEST sequences, characterized by proline, glutamic acid, serine, and threonine enrichment, are structural motifs within proteins that target them for rapid degradation via the ubiquitin-proteasome pathway. Beyond influencing protein degradation, PEST sequences are crucial in regulating angiogenesis and inflammation, essential factors in retinal disease progression. This review focuses on the dual regulatory roles of PEST sequences in VEGFR-2 degradation and stabilization, crucial receptors in angiogenic signaling, as well as their involvement in essential signaling pathways including Notch and JAK/STAT. These findings suggest that PEST sequences could serve as promising new therapeutic targets to control pathological neovascularization and associated inflammatory responses, paving the way for more effective treatments in retinal diseases. Furthermore, advances in gene editing technologies and innovative drug delivery systems enhance the potential for the development of PEST sequence-targeted therapies, offering promising avenues for future clinical applications.