Synthetic and computational efforts towards the development of peptidomimetics and small-molecule SARS-CoV 3CLpro inhibitors.

Severe Acute Respiratory Syndrome (SARS) is a severe febrile respiratory disease caused by the beta genus of human coronavirus, known as SARS-CoV. Last year, 2019-n-CoV (COVID-19) was a global threat for everyone caused by the outbreak of SARS-CoV-2. 3CLpro, chymotrypsin-like protease, is a major cysteine protease that substantially contributes throughout the viral life cycle of SARS-CoV and SARS-CoV-2. It is a prospective target for the development of SARS-CoV inhibitors by applying a repurposing strategy. This review focuses on a detailed overview of the chemical synthesis and computational chemistry perspectives of peptidomimetic inhibitors (PIs) and small-molecule inhibitors (SMIs) targeting viral proteinase discovered from 2004 to 2020. The PIs and SMIs are one of the primary therapeutic inventions for SARS-CoV. The journey of different analogues towards the evolution of SARS-CoV 3CLpro inhibitors and complete synthetic preparation of nineteen derivatives of PIs and ten derivatives of SMIs and their computational chemistry perspectives were reviewed. From each class of derivatives, we have identified and highlighted the most compelling PIs and SMIs for SARS-CoV 3CLpro. The protein-ligand interaction of 29 inhibitors were also studied that involved with the 3CLpro inhibition, and the frequent amino acid residues of the protease were also analyzed that are responsible for the interactions with the inhibitors. This work will provide an initiative to encourage further research for the development of effective and drug-like 3CLpro inhibitors against coronaviruses in the near future.

Osteoarthritis: Prognosis and emerging therapeutic approach for disease management.

Osteoarthritis (OA), a disorder of joints, is prevalent in older age. The contemporary cure for OA is aimed to confer symptomatic relief, consisting of temporary pain and swelling relief. In this paper, we discuss various modalities responsible for the onset of OA and associated with its severity. Inhibition of chondrocytes receptors such as DDR2, SDF-1, Asporin, and CXCR4 by specific pharmacological inhibitors attenuates OA, a critical step for finding potential disease modifying drugs. We critically analyzed recent OA studies with an emphasis on intermediate target molecules for OA intervention. We also explored some novel and safe treatments for OA by considering disease prognosis crosstalk with cellular signaling pathways.

Microtubule-targeting agents augment the toxicity of DNA-damaging agents by disrupting intracellular trafficking of DNA repair proteins.

The paradigm that microtubule-targeting agents (MTAs) cause cell death via mitotic arrest applies to rapidly dividing cells but cannot explain MTA activity in slowly growing human cancers. Many preferred cancer regimens combine a MTA with a DNA-damaging agent (DDA). We hypothesized that MTAs synergize with DDAs by interfering with trafficking of DNA repair proteins on interphase microtubules. We investigated nine proteins involved in DNA repair: ATM, ATR, DNA-PK, Rad50, Mre11, p95/NBS1, p53, 53BP1, and p63. The proteins were sequestered in the cytoplasm by vincristine and paclitaxel but not by an aurora kinase inhibitor, colocalized with tubulin by confocal microscopy and coimmunoprecipitated with the microtubule motor dynein. Furthermore, adding MTAs to radiation, doxorubicin, or etoposide led to more sustained γ-H2AX levels. We conclude DNA damage-repair proteins traffic on microtubules and addition of MTAs sequesters them in the cytoplasm, explaining why MTA/DDA combinations are common anticancer regimens.

Significance of TRAIL/Apo-2 ligand and its death receptors in apoptosis and necroptosis signalling: Implications for cancer-targeted therapeutics.

The human immune defensesystem routinely expresses the tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), which is the most prevalent element for antitumor immunity. TRAIL associates with its death receptors (DRs), DR4 (TRAIL-R1), and DR5 (TRAIL-R2), in cancer cells to initiate the intracellular apoptosis cascade. Accordingly, numerous academic institutions and pharmaceutical companies havetried to exploreTRAIL's capacity to kill tumourcells by producing recombinant versions of it (rhTRAIL) or TRAIL receptor agonists (TRAs) [monoclonal antibody (mAb), synthetic and natural compounds, etc.] and molecules that sensitize TRAIL signalling pathway for therapeutic applications. Recently, several microRNAs (miRs) have been found to activate or inhibit death receptor signalling. Therefore, pharmacological regulation of these miRs may activate or resensitize the TRAIL DRs signal, and this is a novel approach for developing anticancer therapeutics. In this article, we will discuss TRAIL and its receptors and molecular pathways by which it induces various cell death events. We will unravel potential innovative applications of TRAIL-based therapeutics, and other investigated therapeutics targeting TRAIL-DRs and summarize the current preclinical pharmacological studies and clinical trials. Moreover, we will also emphasizea few situations where future efforts may be addressed to modulate the TRAIL signalling pathway.

Isolation of cytotoxic monomeric protein and morin derivatives from Solena amplexicaulis (Lam.) Gandhi.

Solena amplexicaulis (Lam.) Gandhi (family- Cucurbitaceae), is used both in the Indian traditional system and folk medicine to treat several pathophysiological conditions and complex diseases including cancer. The screening of the phytochemicals of this plant (aerial parts) was performed to evaluate their cytotoxic effect against an in vitro cancer model utilising acute promyelocytic leukaemia HL60 cell line. Phytoconstituents were isolated by column chromatography and characterised. The purified protein was extracted, isolated and purified by using standard techniques. The cytotoxicity was evaluated by MTT assay. Spectral analysis revealed the isolated phytochemicals to be Morin-3-O-xyloside (1) and Morin 3-O-glucoside (2). The purified protein (P1) was found to be monomeric having a molecular weight of 30.2 kDa. Watching over 24 h exposure, compound 1 (IC50 1.5 µmol/L), compound 2 (IC50 3.5 µmol/L), and P1 (2.67 µmol/L) exhibited significant cytotoxic activity.

Anti-inflammatory effect of O-methylated flavonol 2-(3,4-dihydroxy-phenyl)-3,5-dihydroxy-7-methoxy-chromen-4-one obtained from Cassia sophera Linn in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Cassia sophera Linn (Family Caesalpiniaceae), popularly known as kasundi, is used both in the Indian traditional system and folk medicine to treat several inflammatory pathologies such as asthma, arthritis and pains. The aim of the present study was to evaluate the scientific basis of anti-inflammatory activity of Cassia sophera ethanol extracts and of an isolated constituent of Cassia sophera. MATERIALS AND METHODS: The anti-inflammatory activity of Cassia sophera was studied using the carrageenan, dextran induced rat paw edema, and cotton pellet induced granuloma in rats. The ethanol extract was administered at the concentrations of 200 and 400mg/kg body weight whereas rhamnetin (RN) was administered at a dose of 10 and 15 mg/kg, b.w. Indomethacin was used as standard drug. RESULTS: The HPLC analysis revealed that good amounts of rhamnetin (0.18%) was present in Cassia sophera.The ethanol extracts at 400mg/kg, showed maximum inhibition of inflammation induced by carrageenan (44%), dextran (40%), cotton pellets (37.47%). On the other hand rhamnetin (15 mg/kg) exhibited maximum anti-inflammatory effect, that is 79 and 33% at the end of 3h with carrageenin, and dextran-induced rat paw edema, respectively. In a chronic test rhamnetin (15 mg/kg) showed 43.32% reduction in granuloma weight. CONCLUSION: The marked inhibitory effect on paw edema and granuloma showed that Cassia sophera possess remarkable anti-inflammatory activity which may be due to rhamnetin at least in part, supporting the folkloric usage of the plant to treat various inflammatory diseases.