Membrane Trafficking and Subcellular Drug Targeting Pathways

Abstract

The movement of micro and macro molecules into and within a cell significantly governs several of their pharmacokinetic and pharmacodynamic parameters, thus regulating the cellular response to exogenous and endogenous stimuli. Trafficking of various pharmacological agents and other bioactive molecules throughout and within the cell is necessary for the fidelity of the cells but has been poorly investigated. Novel strategies against cancer and microbial infections need a deeper understanding of membrane as well as subcellular trafficking pathways and essentially regulate several aspects of the initiation and spread of anti-microbial and anti-cancer drug resistance. Furthermore, in order to avail the maximum possible bioavailability and therapeutic efficacy and to restrict the unwanted toxicity of pharmacological bioactives, these sometimes need to be functionalized with targeting ligands to regulate the subcellular trafficking and to enhance the localization. In the recent past the scenario drug targeting has primarily focused on targeting tissue components and cell vicinities, however, it is the membranous and subcellular trafficking system that directs the molecules to plausible locations. The effectiveness of the delivery platforms largely depends on their physicochemical nature, intracellular barriers, and biodistribution of the drugs, pharmacokinetics and pharmacodynamic paradigms. Most subcellular organelles possess some peculiar characteristics by which membranous and subcellular targeting can be manipulated, such as negative transmembrane potential in mitochondria, intraluminal delta pH in a lysosome, and many others. Many specialized methods, which positively promote the subcellular targeting and restrict the off-targeting of the bioactive molecules, exist. Recent advancements in designing the carrier molecules enable the handling of membrane trafficking to facilitate the delivery of active compounds to subcellular localizations. This review aims to cover membrane trafficking pathways which promote the delivery of the active molecule in to the subcellular locations, the associated pathways of the subcellular drug delivery system, and the role of the carrier system in drug delivery techniques.

[Final accepted version, edited] Redefining genomic view of Clostridioides difficile through pangenome analysis and identification of drug targets from its core genome

“…All 130 proteins were checked for their physicochemical properties. Proteins having more than 100 amino acids, less molecular weight, low pI, negative GRAVY value, high aliphatic index and membrane or cytoplasmic localization were further considered ( 26 - 30 ). All these are the physicochemical properties required for the potent drug target.…”

“…In addition, negative GRAVY value indicated the hydrophilic nature of drug target and higher value of aliphatic index indicates thermostability ( 28 , 29 ). All extracellularly localized proteins were also excluded from the study, these being secreted outside the cell ( 30 ).…”

Potential Stereoselective Binding of Trans-(±)-Kusunokinin and Cis-(±)-Kusunokinin Isomers to CSF1R

“…The rank score was then given a weighted score of 3-2-1 based on the protein's likelihood of drug exposure. The weighted score was determined by target subcellular localization, which was an important factor in drug discovery [48][49][50][51]65]. Thus, we divided proteins into three groups and gave a score according to their role: membrane-bound proteins (3), cytosol proteins (2) and nuclear proteins (1).…”

“…Number 3 stood for membrane-bound proteins, which have the highest chance of drug exposure. Number 2 represented cytoplasmic proteins, whereas number 1 represented proteins inside the nucleus, which have the lowest chance of drug exposure (Figure 2) [36,[48][49][50][51]. The most preferred form was determined by adding the weighted rank scores within the protein group, which is represented as a sum score (weighted) in Table 2.…”

Ensemble of Multiple Classifiers for Multilabel Classification of Plant Protein Subcellular Localization

“…Predicting the subcellular locations of proteins in cells is an important step for providing useful insights into protein functions and the mechanisms underlying various biological processes. Knowledge of protein localization might also provide valuable information for target identification for drug discovery [ 4 , 5 ]. With the advent of high-throughput sequencing technology, innumerable protein sequences are now being progressively identified and submitted to public sequence databases [ 3 ].…”