Drug resistance is a constant threat to malaria control efforts making it important to maintain a good pipeline of new drug candidates. Of particular need are compounds that also block transmission by targeting sexual stage parasites. Mature sexual stages are relatively resistant to all currently used antimalarials except the 8-aminoquinolines that are not commonly used due to potential side effects. Here, we synthesized a new Torin 2 derivative, NCATS-SM3710 with increased aqueous solubility and specificity for Plasmodium and demonstrate potent in vivo activity against all P. berghei life cycle stages. NCATS-SM3710 also has low nanomolar EC50s against in vitro cultured asexual P. falciparum parasites (0.38 ± 0.04 nM) and late stage gametocytes (5.77 ± 1 nM). Two independent NCATS-SM3710/Torin 2 resistant P. falciparum parasite lines produced by growth in sublethal Torin 2 concentrations both had genetic changes in PF3D7_0509800, annotated as a phosphatidylinositol 4 kinase (Pf PI4KIIIβ). One line had a point mutation in the putative active site (V1357G), and the other line had a duplication of a locus containing Pf PI4KIIIβ. Both lines were also resistant to other Pf PI4K inhibitors. In addition NCATS-SM3710 inhibited purified Pf PI4KIIIβ with an IC50 of 2.0 ± 0.30 nM. Together the results demonstrate that Pf PI4KIIIβ is the target of Torin 2 and NCATS-SM3710 and provide new options for potent multistage drug development.
The proteasome plays a vital role throughout the life cycle as Plasmodium parasites quickly adapt to a new host and undergo a series of morphologic changes during asexual replication and sexual differentiation. Plasmodium carries 3 different types of protease complexes: typical eukaryotic proteasome (26S) that resides in the cytoplasm and the nucleus, a prokaryotic proteasome homolog ClpQ that resides in the mitochondria, and a caseinolytic protease complex ClpP that resides in the apicoplast. In silico prediction in conjunction with immunoprecipitation analysis of ubiquitin conjugates have suggested that over half of the Plasmodium falciparum proteome during asexual reproduction are potential targets for ubiquitination. The marked potency of multiple classes of proteasome inhibitors against all stages of the life cycle, synergy with the current frontline antimalarial, artemisinin, and recent advances identifying differences between Plasmodium and human proteasomes strongly support further drug development efforts.
The site-specific action of the drug has been seen from the last eras of the revolution in drug delivery technologies. Drug delivery opportunities by the use of biomimetic nanoparticles like virosomes is a stimulating area of research & development as it demonstrates targeted action by fusion with the target cell. Virosomes are vesicular particles reconstituted from viral envelopes which are non-replicating “artificial viruses” that denotes a unique system for presentation of antigen directly into the host cell. Trials have been created to use them as vaccines or adjuvants moreover as a delivery system for medicine, nucleic acids, or genes. Various attempts have been made to use them as vaccines or adjuvants as well as a delivery system for drugs, nucleic acids, or genes as they are biocompatible, biodegradable, non-toxic and non-autoimmunogenic. The production of vaccines increasingly moved away from living attenuated or inactivated whole organisms to safely killed organism. A virus that is safely killed can be a promising vector because it does not cause infection, and the viral structure allows the virosome to identify different components of its target cells. Pevion's virus-like particle (VLP) vaccine technology, called virosomes, and its architecture is specifically designed to produce safe and efficient vaccine subunits. Virosome-based vaccination is effective in reliable regulatory and safety records as well as the feasibility of upgrading production and has been approved in more than 40 countries, including infants and older people. The prospect of drug delivery and targeting using virosomes is a vital area of research and development. This review pinpoints the various aspect of virosome and will be a milestone for the researchers in the field of drug delivery.
Pharmaceutical research has developed various new types of innovative forms of drug delivery. Advancement in current drug delivery methods has led to the development of numerous new revolutionary technologies that support safe and efficient formulations over existing ones. Novasome technology is one of the latest liposome developments that have overcome many of the liposomal drug delivery system-related problems. This provides a seven bilayer membrane which is capable of absorbing water-soluble as well as insoluble drugs. The improved efficiency of entrapping drugs with good encapsulation features enables better frequency of dosing, which can be accomplished through the high shear system. These find their applications in diverse fields such as cosmetics, chemicals, personal care, food, pharmacy, and agrochemicals. Several products have already been launched into the market using this technology with an additional launch plan. Due to its depth of penetration, novasomes have been one of the most popular derma cosmetics. It is being studied continuously to obtain improved release characteristics. The prospect of drug delivery and targeting using novasomes is an important area of research and development. This review pinpoints the various aspect of the novasome and will be a milestone for the researchers in the area of drug delivery.
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