Unlocking the potential of PROTACs: A comprehensive review of protein degradation strategies in disease therapy.

The technology known asPROTACs (PROteolysisTArgeting Chimeras) is a method of protein degradation. Utilising bifunctional small molecules, the ubiquitin-proteosome system (UPS) is used to induce the ubiquitination and degradation of target proteins. In addition to being novel chemical knockdown agents for biological studies that are catalytic, reversible, and rapid, PROTACs used in the treatment for disorders like cancer, immunological disorders, viral diseases, and neurological disorders. The protein degradation field has advanced quickly over the last two years, with a significant rise in research articles on the subject as well as a quick rise in smallmolecule degraders that are currently in or will soon enter the clinical stage. Other new degrading technologies, in addition to PROTAC and molecular glue technology, are also emerging rapidly. In this review article, we mainly focuses on various PROTAC molecules designed with special emphasis on targeted cellular pathways for different diseases i.e., cancer, Viral diseases Immune disorders, Neurodegenerative diseases, etc. We discussed about new technologies based on PROTACs such as Antibody PROTAC, Aptamers, Dual target, Folate caged, TF PROTAC, etc. Also, we listed out the PROTACs which are in clinical trials.

Ethnological validation of Ashwagandha (Withania somnifera L. Dunal) ghrita as 'Vajikarana Rasayana': In-silico, in-vitro and in-vivoapproach.

ETHNOPHARMACOLOGICAL RELEVANCE: Processing cow ghee (clarified butterfat) with therapeutic herbs, i.e. ghrita, is recognized for augmenting the therapeutic efficacy of plant materials. Ashwagandha ghrita (AG) is an effective Ayurvedic formulation consisting of Indian ginseng, i.e., Withania somnifera (L.) Dunal, the main constituent used to treat infertility, weakness, gynaecological disorders, and general debility. OBJECTIVES: The present investigation was undertaken to corroborate the ethnopharmacological claim of AG as 'Vajikarana Rasayana' for its aphrodisiac potential using bioinformatics (in-silico) and experimental (in-vitro and in-vivo) approaches. METHODS: AG was formulated as per the methods reported in Ayurved sarsangraha. AG was further subjected to HPLC, GCMS analysis, and biological (acute toxicity and aphrodisiac) assessment per the standard procedures. Thirty-eight bioactives of Indian ginseng were subjected to computational studies (molecular docking and network pharmacology) to confirm the plausible mechanism. RESULTS: AG was found to be safe up to 2000 mg/kg body wt., and it showed dose-dependent upsurge (p < 0.01 and p < 0.05, wherever necessary) in mount and intromission frequency, genital grooming, and anogenital sniffing at 150 and 300 mg/kg body weight suggesting aphrodisiac activity. In-vitro studies demonstrated significant relaxation of the Corpus Cavernosal Smooth Muscle at all concentrations in a dose-dependent manner. Furthermore, the results of molecular modelling studies were in agreement with the biological activity and showed interaction with phosphodiesterase-5 as a possible target. CONCLUSION: AG exhibited an aphrodisiac effect and substantiated the traditional claim of Indian ginseng-based ghrita formulation as 'Vajikarana Rasayana'.

Dual acting acid-cleavable self-assembling prodrug from hyaluronic acid and ciprofloxacin: A potential system for simultaneously targeting bacterial infections and cancer.

The incidence and of bacterial infections, and resulting mortality, among cancer patients is growing dramatically, worldwide. Several therapeutics have been reported to have dual anticancer and antibacterial activity. However, there is still an urgent need to develop new drug delivery strategies to improve their clinical efficacy. Therefore, this study aimed to develop a novel acid cleavable prodrug (HA-Cip) from ciprofloxacin and hyaluronic acid to simultaneously enhance the anticancer and antibacterial properties of Cip as a superior drug delivery system. HA-Cip was synthesised and characterised (FT-IR, HR-MS, and H1 NMR). HA-Cip generated stable micelles with an average particle size, poly dispersion index (PDI) and zeta potential (ZP) of 237.89 ± 25.74 nm, 0.265 ± 0.013, and -17.82 ± 1.53 mV, respectively. HA-Cip showed ≥80 % cell viability against human embryonic kidney 293 cells (non-cancerous cells), ˂0.3 % haemolysis; and a faster pH-responsive ciprofloxacin release at pH 6.0. HA-Cip showed a 5.4-fold improvement in ciprofloxacin in vitro anticancer activity against hepatocellular cancer (HepG2) cells; and enhanced in vitro antibacterial activity against Escherichia coli and Klebsiella pneumoniae at pH 6.0. Our findings show HA-Cip as a promising prodrug for targeted delivery of ciprofloxacin to efficiently treat bacterial infections associated, and/or co-existing, with cancer.

Liposomal delivery systems and their applications against Staphylococcus aureus and Methicillin-resistant Staphylococcus aureus.

Liposomal delivery systems have been widely explored for targeting superbugs such as S. aureus and MRSA, overcoming antimicrobial resistance associated with conventional dosage forms. They have the significant advantage of delivering hydrophilic and lipophilic antimicrobial agents, either singularly as monotherapy or in combination as combination therapy, due to their bilayers with action-site-specificity, resulting in improved targeting compared to conventional dosage forms. Herein, we present an extensive and critical review of the different liposomal delivery systems employed in the past two decades for the delivery of both antibiotics of different classes and non-antibiotic antibacterial agents, as monotherapy and combination therapy to eradicate infections caused by S. aureus and MRSA. The review also identifies future research and strategies potentiating the applications of liposomal delivery systems against S. aureus and MRSA. This review confirms the potential application of liposomal delivery systems for effective delivery and specific targeting of S. aureus and MRSA infections.

Advances in sepsis diagnosis and management: a paradigm shift towards nanotechnology.

Sepsis, a dysregulated immune response due to life-threatening organ dysfunction, caused by drug-resistant pathogens, is a major global health threat contributing to high disease burden. Clinical outcomes in sepsis depend on timely diagnosis and appropriate early therapeutic intervention. There is a growing interest in the evaluation of nanotechnology-based solutions for sepsis management due to the inherent and unique properties of these nano-sized systems. This review presents recent advancements in nanotechnology-based solutions for sepsis diagnosis and management. Development of nanosensors based on electrochemical, immunological or magnetic principals provide highly sensitive, selective and rapid detection of sepsis biomarkers such as procalcitonin and C-reactive protein and are reviewed extensively. Nanoparticle-based drug delivery of antibiotics in sepsis models have shown promising results in combating drug resistance. Surface functionalization with antimicrobial peptides further enhances efficacy by targeting pathogens or specific microenvironments. Various strategies in nanoformulations have demonstrated the ability to deliver antibiotics and anti-inflammatory agents, simultaneously, have been reviewed. The critical role of nanoformulations of other adjuvant therapies including antioxidant, antitoxins and extracorporeal blood purification in sepsis management are also highlighted. Nanodiagnostics and nanotherapeutics in sepsis have enormous potential and provide new perspectives in sepsis management, supported by promising future biomedical applications included in the review.

Design, synthesis and pharmacological evaluation of pyrimidobenzothiazole-3-carboxylate derivatives as selective L-type calcium channel blockers.

L-type voltage gated calcium channels play essential role in contraction of various skeletal and vascular smooth muscles, thereby plays important role in regulating blood pressure. Dihydropyridine receptors have been targeted for development of newer antihypertensive agents, one of the structurally analogs nucleus dihydropyrimidines have been reported earlier by us as a potential agent toward development of calcium channel modulator. A pre-synthetic QSAR was run and on the basis of structure activity relationship a series of twenty three molecules was synthesized and studied by myosin light chain kinase assay (MLCK), Angiotensin Converting Enzyme (ACE) colorimetric assay, non-invasive blood pressure (NIBP) and invasive blood pressure (IBP) methods. Molecules with significant efficacy were studied for their single crystal X-ray diffraction, molecular docking, molecular dynamics and post-synthetic QSAR. The NIBP and IBP methods screened molecules with better percentage inhibition versus time compared to standard drug Nifedipine. The lead compound ethyl 2-methyl-4-(3-nitrophenyl)-4H-pyrimido [2,1-b] [1,3] benzothiazole-3-carboxylate (26) presented a triclinic structure with polymeric chain packing in lattice. 26 exhibited IC50 on MLCK assay of 2.1±1.7 µM with selectivity of L-type calcium channels and comparative to Nifedipine. It offered satisfactory physicochemical properties with partition coefficient of (ClogP) 4.64. Its pharmacokinetic profile is also good with Cmax at 0.40 µg/ml by oral route with Tmax reaching in 0.5 h which means in 30 min. 26 also exhibits superior t1/2 of 5.4 h and oral bioavailability of (F) 56.75% with an AUC0-∞ of 0.84 µg h/ml. Molecular docking studies indicates toward the interaction of lead compound via hydrogen bonds with Lys144, Glu181 and Asp183, it forms the Van der Walls interactions with Ser18, Asp20, Asn187, Pro185, Glu180, Glu181 and Arg10 with Glide score and Glide energy to be -3.602 and -47.098, respectively. Post-synthetic QSAR of newly synthesized molecules indicates toward improvement with respect to steric descriptor which contributed negatively in former series.

Smallest organism; highest threat.

Ever since the discovery of virus in beginning of 20th century, infections caused by these organisms have captured attention of researchers. The evolution of viruses is still a controversy, even same for their categorization in either living or non-living. It is clear that besides many controversies virus remains challenging to treat as well as to control in some extent. Though vaccines are available as prophylactic tool and antiviral drugs for treatment, still virus exist in host cells if they successfully invade biological machinery. Now it remains as challenge to treat these smallest organisms with high degree of efficacy and safety. To answer the demand of the present world there is urgent need of more potent and novel drugs for treatment and vaccines to prevent infection. Answer to this problem will definitely reduce casualties occurring worldwide. This review presents few of the pandemics, their causative agents, current status of treatment and future prospective.