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As of September 2021, 117 COVID-19 vaccines are in clinical development, and 194 are in preclinical development as per the World Health Organization (WHO) published draft landscape. Among the 117 vaccines undergoing clinical trials, the major platforms include protein subunit; RNA; inactivated virus; viral vector, among others. So far, USFDA recognized to approve the Pfizer-BioNTech (Comirnaty) COVID-19 vaccine for its full use in individuals of 16 years of age and older. Though the approved vaccines are being manufactured at a tremendous pace, the wealthiest countries have about 28% of total vaccines despite possessing only 10.8% of the total world population, suggesting an inequity of vaccine distribution. The review comprehensively summarizes the history of vaccines, mainly focusing on vaccines for SARS-CoV-2. The review also connects relevant topics, including measurement of vaccines efficacy against SARS-CoV-2 and its variants, associated challenges, and limitations, as hurdles in global vaccination are also kept forth.

Background: The rapid spread of SARS-CoV-2 has caused havoc and panic among individuals, which has further worsened due to the unavailability of a proven drug(s) regime. Objective: The current work involves drug repurposing from the pool of USFDA approved drugs involving in silico virtual screening technique against COVID-19. Materials and Methods: Methodology involves virtual screening of 8548 FDA approved drugs against target protein endoribonuclease NendoU (Nsp15) (PDB ID: 6VWW). Results: Virtual screening-based analysis enabled us to identify four drugs, Eprosartan, Inarigivir soproxil, Foretinib, and DB01813 that could plausibly target Nsp15 against COVID-19 disease. Conclusion: The work offers the scope to corroborate the findings via in vitro and in vivo techniques to identify the potential of selected leads against COVID-19. The outcome may also help in tracing their molecular mechanism(s) in addition to their development at the clinical level in the future.

The kidney is essential for the physiological functions of the body. When exposed to high concentrations of toxins, these may induce the toxicity of the kidney (kidney injury), leading to renal failure and precipitating a condition called nephrotoxicity. The toxicity may result from hemodynamic changes and directly harm the cells and tissue, and causes obstruction of renal excretion. Nephrotoxicity can also be induced by renal impairment leads to kidney-specific detoxification and diminished kidney function by ischemia and toxicants/drugs. Considering the possible damage to kidneys by drugs, patients are using the naturally derived substance, including herbal drugs or nutraceuticals. However, the safety concerns of herbal drugs and formulation in inducing kidney injury are an area of research. The present review is a concerted effort to assemble information mainly focusing on the kidney injury, its comprehensive categorization, i.e., mechanism of interaction of various enzyme systems of kidneys with drugs of herbal and synthetic origin and their outcomes. Moreover, the review also put forth the details of herbal drug that precipitate kidney injury and ameliorate it. The review is being put forward with an incentive to provide researchers with a comprehensive and updated literature on kidney injury by drugs of natural and synthetic origin and their molecular targets in the kidney.

The mechanisms by which drugs act are different and unique to each class as they involve interactions with pharmacological receptors, enzymes, ion channels, and cellular transport processes. Hormones, neurotransmitters, and autocoids are natural chemical messengers that have a role in physiological and pathological regulatory processes. The interpretation of their action is determined by the localization and functional capacity of the specific receptor with which the “first messenger” interacts and the concentration of the chemical to which the receptor is exposed.

Historically ever since the existence of humans on this planet the process of drug discovery was started by trial and error method. Initially they tested the natural products on self to understand the effects. Serendipity played a great role in the evolution of drug discovery. Isolation of active ingredients from plants started in the early nineteenth century. The advances in the field of chemical and biological sciences started the modern drug discovery and development. The regulatory processes became stringent due to some adverse events in the second half of the twentieth century. Currently the digital and disruptive technologies are changing the scenario of drug discovery and development and producing efficacious and safe drugs.

This chapter reviews the literature on the various factors (time-consuming processes, regulatory requirements, high attrition rate in phase III clinical trials and decrease in R&D productivity) contributed to increase the average cost of drug discovery. A better interaction between the stakeholders, i.e. pharmaceutical industry, academia, regulatory authorities and end users, results in efficacious, safe and affordable drugs to the benefit of the society.

The expanding horizon of nanotechnology has covered most of the parts of our life including general household items to drug delivery and therapeutics. The progresses made in the nanotechnology field provided us some of the clinically useful nano-based products apart from the more than 50 products in pipeline. However, as these products are intended for human use, they also raise some critical safety concerns primarily due to their altered physicochemical properties different from the bulk. Further, the use of nanocarriers has also been found to be associated with different unwanted toxicological observations which depends on different factors. Hence, the safe and efficacious use of these nanocarriers strictly entails the comprehensive and thorough knowledge of the toxicological potential of nanocarriers. Further, the harmonious integration of academia, researcher, industries and regulatory bodies is warranted to ensure the proper regulation of their use.

A series of triphenyl substituted pyrimidines as analogous of colchicine and combretastatin A-4 was synthesized and evaluated for the antiproliferative potential. The compounds were screened against MDA-MB-231, HCT-116 and HT-29 cell lines using MTT assay. Most of the compounds displayed antiproliferative activity in low to sub micro molar concentration. Amongst the synthesized derivatives, compounds HK-2, HK-10 and HK-13 were found to be effective against all the three cancer cell lines. HK-2 exhibited IC50 values of 3.39 µM, 4.78 µM and 4.23 µM, HK-10 showed IC50 values of 0.81 µM, 5.89 µM, 4.96 µM and HK-13 showed IC50 values 3.24 µM, 4.93 µM and 4.73 µM against MDA-MB-231, HCT-116 and HT-29 cancer cell lines, respectively. HK-10 was found to be the most potent compound in the series with IC50 values of 0.81 µM against MDA-MB-231. In the cell cycle analysis, HK-2 and HK-10 showed cell arrest at G2/M phase of the cell cycle while HK-13 inhibited cell growth at the G1/G0 phase. All the three compounds showed cell death induced through apoptosis. In the docking studies, HK-2, HK-10 and HK-13 were found to fit well in the colchicine binding site of the tubulin. Some of the compounds in the current series were found to be promising against all the three cancer cell lines and may act as potent leads for further development.

Nature, which remains a central drug discovery pool, is always looked upon to find a putative druggable lead. The natural products and phytochemical derived from plants are essential during a global health crisis. This class represents one of the most practical and promising approaches to decrease pandemic's intensity owing to their therapeutic potential. The present manuscript is therefore kept forth to give the researchers updated information on undergoing research in allied areas of natural product-based drug discovery, particularly for Covid-19 disease. The study briefly shreds evidence from in vitro and in silico researches done so far to find a lead molecule against Covid-19. Following this, we exhaustively explored the concept of chemical space and molecular similarity parameters for the drug discovery about the lead(s) generated from in silico-based studies. The comparison was drawn using FDA-approved anti-infective agents during 2015-2020 using key descriptors to evaluate druglike properties. The outcomes of results were further corroborated using Molecular Dynamics studies which suggested the outcomes in alignment with chemical space ranking. In a nutshell, current research work aims to provide a holistic strategic approach to drug design, keeping in view the identified phytochemicals against Covid-19.

The review summarizes chloroquine (CQ) and its safer derivative hydroxychloroquine (HCQ) and its utility in Covid-19. Recently this well-established drug made its way back to the headlines during the SARS-CoV-2 pandemic. This led to an upsurge in the scientific arena with multiple research and review articles along with expert opinions and commentaries. The HCQ has received mixed judgements so far about its efficacy for Covid-19 patients in a limited trial conducted all across the Globe. The purpose of our article is to put forth the history, pharmacodynamics, and pharmacokinetics, along with the existing studies favouring and disapproving the role of HCQ in the treatment of Covid-19. We grouped HCQ use at three various stages. The stages include the use of HCQ for i. prophylactic use by asymptomatic health workers or peoples at higher risk; ii. patients having mild symptoms; iii. patients with extreme symptoms. The review critically discusses the underlying plausible reasons and mechanisms exploring HCQ in prophylactic management or treatment of SARS-CoV-2. Furthermore, we have critically analysed the reported pharmacokinetic parameters and compiled the proponent, opponent, or neutral opinions on the use of HCQ in Covid-19. Authors discretion is to conduct more studies considering the optimal dosing regimen and pharmacokinetics assessment., Graphical abstract Image 1

The symptoms and signs of Covid-19 caused by SARS-CoV-2 in severe conditions can cause multiple organ failure and fatality via a plethora of mechanisms, and it is essential to discover the efficacious and safe drug. For this, a successful strategy is to inhibit in different stages of the SARS-CoV-2 life cycle and host cell reactions. The current review briefly put forth the summary of the SARS-CoV-2 pandemic and highlight the critical areas of understanding in genomics, proteomics, medicinal chemistry, and natural products derived drug discovery. The review further extends to briefly put forth the updates in the drug testing system, biologics, biophysics, and their advances concerning SARS-CoV-2. The salient features include information on SARS-CoV-2 morphology, genomic characterization, and pathophysiology along with important protein targets and how they influence the drug design and development against SARS-CoV-2 and a concerted and integrated approach to target these stages. The review also gives the status of drug design and discovery to identify the drugs acting on critical targets in SARS-CoV-2 and host reactions to treat Covid-19., Graphical abstract Image 1, Highlights • SARS-CoV-2 is the seventh coronavirus strain reported to infect Homo sapiens. • Remedesvir has been approved for the treatment of Covid-19. • The druggable targets of the virus include spike protein, membrane protein, protease, envelope protein, hemagglutinin esterase, nucleocapsid protein, and helicase proteins. • Host and virus interactions result in inflammation, and multiple organs damage are plausible switches for drugs to act to combat Covid-19. • Apart from synthetic drugs, active ingredients derived from natural/herbal and fruits are also being exploited for their effectiveness against SARS-CoV-2.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a positive-sense, single-stranded RNA virus that causes the potentially lethal Covid-19 respiratory tract infection. It does so by binding to host cell angiotensin converting enzyme 2 (ACE2) receptors, leading to endocytosis with the receptor, and subsequently using the host cell’s machinery to replicate copies of itself and invade new cells. The extent of the spread of infection in the body is dependent on the pattern of ACE2 expression and overreaction of the immune system. Additionally, by inducing an imbalance in the renin-angiotensin-aldosterone system (RAAS) and the loss of ACE2 would favour the progression of inflammatory and thrombotic processes in the lungs. No drug or vaccine has yet been approved to treat human coronaviruses. Hundreds of clinical trials on existing approved drugs from different classes acting on a multitude of targets in the virus life cycle are ongoing to examine potential effectiveness for the prevention and treatment of the infection. This review summarizes the SARS-CoV-2 virus life cycle in the host cell and provides a biological and pathological point of view for repurposed and experimental drugs for this novel coronavirus. The viral lifecycle provides potential targets for drug therapy., Graphical abstract Unlabelled Image, Highlights • ACE2 is a cellular functional receptor for SARS-CoV-2. • Ang (1-7) counterbalances the adverse actions of Ang II on the heart and blood vessels. • The ss-positive sense RNA undergoes translation by using host cell machinery. • Cell attachment, translation, replication and inflammation are drug targets for Covid-19. • The RAAS inhibitors in the pathogenesis of Covid-19 is overly complex and controversial.

Different types of nanomaterials possess excellent physical and chemical properties. Nanoparticles (NPs) have been implicated for use in drug and gene delivery. Several in vitro and in vivo studies suggest the cytotoxic and proinflammatory potential of NPs. Further, parenteral administration of NPs results in their accumulation in several tissues. The possible mechanism of toxicity appears to be production of free radicals, mitogen activated protein kinase (MAPK) activation and translocation of transcription factors from cytoplasm to nucleus. This leads to induction of apoptosis, growth arrest, and cell death. Further, factors like nuclear factor-κB (NF-κB) lead to production of proinflammatory cytokines. The present review focuses on the cytotoxicity, biodistribution, and mechanism of NPs toxicity with special emphasis on carbon nanotubes (CNTs) toxicity.

We assessed whether cysteinyl leukotrienes mediate the vasoconstrictor responses to angiotensin II and endothelin-1 in the mesenteric vascular bed of Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) perfused ex vivo at a constant flow rate of 5 ml/min with Krebs buffer. Maximal perfusion pressure response ( Emax) but not EC50values to angiotensin II ( P < 0.001) and endothelin-1 ( P < 0.01) were significantly higher in the SHR, whereas the responses to potassium chloride remained unchanged. Inclusion of the selective 5-lipoxygenase inhibitor AA-861 or the cysteinyl leukotriene receptor antagonist MK-571 significantly reduced the vasoconstrictor responses to angiotensin II but not to endothelin-1 and potassium chloride. The reduction in Emaxto angiotensin II was more pronounced in SHR ( P < 0.001) than in WKY ( P < 0.05) rats. Cysteinyl leukotrienes LTC4-, LTD4-, and LTE4(1 μM)-evoked vasoconstrictor responses were significantly higher in SHR ( P < 0.05), whereas LTB4failed to evoke any response in either strain. These data suggest that 5-lipoxygenase metabolites, particularly cysteinyl leukotrienes, contribute to the exaggerated vasoconstrictor responses to angiotensin II but not to endothelin-1.

Abstract: Increased incidences of cardio-vascular complications in diabetic conditions are a major concern. Endothelin-1 (ET-1) is an important regulator of vascular contractility, and its effects are mediated through ETA and ETB. Previous data from the lab indicates that GPCR mediate contractile responses are enhanced and the present study is aimed to extend the hypothesis that ETA receptor mediated contractile responses of ET-1 under insulin-resistant condition are enhanced. Methods: Male Sprague-Dawley (SD) rats were kept on high-fat diet (HFDIRR, 8 weeks) for inducing insulin-resistance. Further, b-cell specific toxin streptozotocin (STZ, 50 mg/kg; i.p.) was used to induce hypoinsulinemia in rats. The responses of ET-1, ACh, KCl and Ang -II were recorded in the concentration-dependent manner in the thoracic aorta of rats. Specific ETA receptor antagonist, BMS182874 was used to confirm the findings. Specific binding of [3H]-BQ123 was performed to determine the characteristics of ETA receptors. Biochemical parameters were measured and induction of insulin-resistance was confirmed by intra-peritoneal glucose tolerance test (IPGTT). Results: ET-1 mediated contractile response (4541 ± 274 mg/mm2 (mean ± s.e.m. (n=8)) was significantly higher in insulin-resistant rats, while that of KCl unchanged. Tempol (100μM) restored the ET-1 mediated contractions in HFDIRR (4541 ± 274 vs 3406 ± 252.8 mg/mm2; p < 0.001; (n=5)). BMS182874 restored NO-mediated endothelium-dependent ACh relaxation in HFDIRR. The specific binding of [3H]-BQ123 to ETA receptors (112.35 ± 5.19 vs. 39.74 ± 4.04 f mol/mg; P < 0.001; (n=5)) was increased in HFDIRR. Conclusions: Insulin-resistance up-regulates ETA receptor may be responsible enhanced ET-1 mediated contractility of the thoracic aorta.

To assess angiotensin II type 2 receptor-mediated responses in thoracic aorta of streptozotocin-induced diabetic rats.The concentration-dependent relaxation response (in the presence of an AT1 receptor blocker) to angiotensin II (Ang II) was studied in phenylephrine (PE) or potassium chloride (KCl) precontracted rat thoracic aortic rings isolated from male Sprague-Dawley rats pretreated with streptozotocin (65 mg/kg i.p.) or vehicle 8 weeks prior to the study.Ang II-induced relaxation response (% relaxation), evident only in the presence of an AT1 receptor blocker, was significantly enhanced in aortic rings isolated from diabetic (55%) compared to control (25%) rats. Tempol (100 micromol/l) augmented the relaxation response in aortic rings isolated from diabetic (80%) but not control (28%) rats. N-nitro-l-arginine methyl ester (L-NAME) (100-300 micromol/l) [a nitric oxide (NO) synthase inhibitor] partially inhibited the relaxation response in diabetic (25%) and control (15%) rats. However, l-NAME (100 micromol/l) and glipizide or butanedione monoxime (1 micromol/l) (ATP-sensitive K channel blockers) together completely blocked the relaxation response. [H]Ang II saturation binding at the AT2 receptor was enhanced in aortic membranes from diabetic [maximum binding capacity, (Bmax)=1.14 +/- 0.06 fmol/mg protein] compared to control rats (Bmax=0.75 +/- 0.03 fmol/mg protein), with no change in the dissociation equilibrium constant (Kd) value (2.55 +/- 0.12 versus 2.22 +/- 0.15 nmol/l).The results suggest enhanced AT2-receptor density and function [mediated by a nitric oxide and ATP-sensitive K channel-dependent relaxation response (in presence of an AT1 receptor blocker)] in thoracic aorta isolated from diabetic rats. This could be a compensatory mechanism, which may be therapeutically exploited.

Objective To assess whether superoxide anions mediate vasoconstrictor responses to agonists in blood vessels of spontaneously hypertensive rats (SHRs). Methods The effect of the superoxide dismutase mimetic, 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (tempol), on responses to angiotensin II (Ang II), endothelin-1, phenylephrine and potassium chloride was determined in aortic rings and perfused mesenteric vascular beds (MVB) of adult male rats of the Sprague-Dawley, Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) strains. The effect of tempol on Ang II-evoked superoxide production was assessed in aortic rings. Results There were no differences in the maximum tension (E max ) attained in response to agonists, but the negative logarithm of the concentration required to produce 50% of the maximal response (EC 50 ) for Ang II was lower (P < 0.05) in aortic rings of SHRs. In the MVBs of SHRs, the E max but not the EC 50 values attained in response to Ang II, endothelin-1 and phenylephrine were greater. Tempol significantly and selectively reduced the E max of Ang II in both aorta and MVB preparations with intact endothelium. The reduction in E max attained in response to Ang II was more pronounced in SHRs (P < 0.01) than in WKY rats (P < 0.05) or Sprague-Dawley rats (P < 0.05). The inhibitory effect of tempol was absent when a nitric oxide synthase inhibitor was included or endothelium was denuded. A significant increase in lucigenin chemiluminescence evoked by Ang II in both intact and endothelium-denuded aortic rings of SHRs was abolished when tempol was included in the buffer. Conclusions These data suggest that increased superoxide anions mediate vasoconstrictor responses to Ang II, but not to other agonists, in an endothelium-dependent manner, by quenching vasodilatory mediator, nitric oxide. This may account for the exaggerated vasoconstrictor responses to Ang II in SHRs.