A CD38-directed, single-chain T-cell engager targets leukemia stem cells through IFN-γ-induced CD38 expression.

ABSTRACT: Treatment resistance of leukemia stem cells (LSCs) and suppression of the autologous immune system represent major challenges to achieve a cure in acute myeloid leukemia (AML). Although AML blasts generally retain high levels of surface CD38 (CD38pos), LSCs are frequently enriched in the CD34posCD38neg blast fraction. Here, we report that interferon gamma (IFN-γ) reduces LSCs clonogenic activity and induces CD38 upregulation in both CD38pos and CD38neg LSC-enriched blasts. IFN-γ-induced CD38 upregulation depends on interferon regulatory factor 1 transcriptional activation of the CD38 promoter. To leverage this observation, we created a novel compact, single-chain CD38-CD3 T-cell engager (BN-CD38) designed to promote an effective immunological synapse between CD38pos AML cells and both CD8pos and CD4pos T cells. We demonstrate that BN-CD38 engages autologous CD4pos and CD8pos T cells and CD38pos AML blasts, leading to T-cell activation and expansion and to the elimination of leukemia cells in an autologous setting. Importantly, BN-CD38 engagement induces the release of high levels of IFN-γ, driving the expression of CD38 on CD34posCD38neg LSC-enriched blasts and their subsequent elimination. Critically, although BN-CD38 showed significant in vivo efficacy across multiple disseminated AML cell lines and patient-derived xenograft models, it did not affect normal hematopoietic stem cell clonogenicity and the development of multilineage human immune cells in CD34pos humanized mice. Taken together, this study provides important insights to target and eliminate AML LSCs.

Capturing Sialyl-glycan on Live Cancer Cells by Tailored Boronopeptide.

Boronic acid-containing molecules are substantially popularized in chemical biology and medicinal chemistry due to the broad spectrum of covalent conjugations as well as interaction modules offered by the versatile boron atom. Apparently, the WGA peptide (wheat germ agglutinin, 62-73), which shows a considerably low binding affinity to sialic acid, turned into a selective and >5 folds potent binder with the aid of a suitable boronic acid probe installed chemoselectively. In silico studies prompted us to install BA probes on the cysteine residue, supposedly located in close proximity to the bound sialic acid. In vitro studies revealed that the tailored boronopeptides show enhanced binding ability due to the synergistic recognition governed by selective non-covalent interactions and cis-diol boronic acid conjugation. The intense binding is observed even in 10 % serum, thus enabling profiling of sialyl-glycan on cancer cells, as compared with the widely used lectin, Sambucus nigra. The synergistic binding mode between the best boronopeptide (P3) binder and sialic acid was analyzed via 1 H and 11 B NMR.

Sulfonyl Diazaborine 'Click' Chemistry Enables Rapid and Efficient Bioorthogonal Labeling.

Finding an ideal bioorthogonal reaction that responds to a wide range of biological queries and applications is of great interest in biomedical applications. Rapid diazaborine (DAB) formation in water by the reactions of ortho-carbonyl phenylboronic acid with α-nucleophiles is an attractive conjugation module. Nevertheless, these conjugation reactions demand to satisfy stringent criteria for bioorthogonal applications. Here we show that widely used sulfonyl hydrazide (SHz) offers a stable DAB conjugate by combining with ortho-carbonyl phenylboronic acid at physiological pH, competent for an optimal biorthogonal reaction. Remarkably, the reaction conversion is quantitative and rapid (k2 >103  M-1 s-1 ) at low micromolar concentrations, and it preserves comparable efficacy in a complex biological milieu. DFT calculations support that SHz facilitates DAB formation via the most stable hydrazone intermediate and the lowest energy transition state compared to other biocompatible α-nucleophiles. This conjugation is extremely efficient on living cell surfaces, enabling compelling pretargeted imaging and peptide delivery. We anticipate this work will permit addressing a wide range of cell biology queries and drug discovery platforms exploiting commercially available sulfonyl hydrazide fluorophores and derivatives.

Cardiovascular Complications of Obstructive Sleep Apnea in the Intensive Care Unit and Beyond.

Obstructive sleep apnea (OSA) is a common disease with a high degree of association with and possible etiological factor for several cardiovascular diseases. Patients who are admitted to the Intensive Care Unit (ICU) are incredibly sick, have multiple co-morbidities, and are at substantial risk for mortality. A study of cardiovascular manifestations and disease processes in patients with OSA admitted to the ICU is very intriguing, and its impact is likely significant. Although much is known about these cardiovascular complications associated with OSA, there is still a paucity of high-quality evidence trying to establish causality between the two. Studies exploring the potential impact of therapeutic interventions, such as positive airway pressure therapy (PAP), on cardiovascular complications in ICU patients are also needed and should be encouraged. This study reviewed the literature currently available on this topic and potential future research directions of this clinically significant relationship between OSA and cardiovascular disease processes in the ICU and beyond.

Pyruvate kinase M2 in chronic inflammations: a potpourri of crucial protein-protein interactions.

Chronic inflammation (CI) is a primary contributing factor involved in multiple diseases like cancer, stroke, diabetes, Alzheimer's disease, allergy, asthma, autoimmune diseases, coeliac disease, glomerulonephritis, sepsis, hepatitis, inflammatory bowel disease, reperfusion injury, and transplant rejections. Despite several expansions in our understanding of inflammatory disorders and their mediators, it seems clear that numerous proteins participate in the onset of CI. One crucial protein pyruvate kinase M2 (PKM2) much studied in cancer is also found to be inextricably woven in the onset of several CI's. It has been found that PKM2 plays a significant role in several disorders using a network of proteins that interact in multiple ways. For instance, PKM2 forms a close association with epidermal growth factor receptors (EGFRs) for uncontrolled growth and proliferation of tumor cells. In neurodegeneration, PKM2 interacts with apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) to onset Alzheimer's disease pathogenesis. The cross-talk of protein tyrosine phosphatase 1B (PTP1B) and PKM2 acts as stepping stones for the commencement of diabetes. Perhaps PKM2 stores the potential to unlock the pathophysiology of several diseases. Here we provide an overview of the notoriously convoluted biology of CI's and PKM2. The cross-talk of PKM2 with several proteins involved in stroke, Alzheimer's, cancer, and other diseases has also been discussed. We believe that considering the importance of PKM2 in inflammation-related diseases, new options for treating various disorders with the development of more selective agents targeting PKM2 may appear.

The impact of gender, age, race/ethnicity, and stage on quality of life in a spectrum of cutaneous lymphomas.

PURPOSE: Cutaneous lymphomas (CLs) are a group of rare, potentially disfiguring and disabling cancers that can have a significant impact on quality of life (QoL). While previous studies have shown that mycosis fungoides (MF) and Sézary syndrome (SS) impair QoL, the effect of other types of CL on QoL has not been evaluated. OBJECTIVE: To determine the impact of disease on QoL in all CL patients and to assess how QoL between the CL sub-types varies by demographic and clinical factors. METHODS: The Cutaneous Lymphoma Distress Questionnaire (CL-DQ) was used to assess QoL. All CL patients seen in a multidisciplinary CL clinic were screened for eligibility. Questionnaire responses were collected over a 22-month period between 2017 and 2019. A cross-sectional analysis of CL-DQ scores from an initial visit was performed to determine the effect of disease on QoL across CL sub-types and the potential impact of patient demographics, CL sub-type, and type of treatment. RESULTS: The study population consisted of 151 patients presenting with distinct types of cutaneous B- and T-cell lymphomas. Notable across the study population were the findings of frustration (44%), worry about progress/spread (43%), itching/pruritus (32%), and embarrassment/shame (28%). QoL was found to be most negatively affected in SS patients, females, younger patients, Black patients, and those with advanced stages of MF/SS. CONCLUSIONS: Impairment of QoL due to CL correlates with gender, age, race/ethnicity, and stage of MF/SS. While the negative impact on QoL is most pronounced in SS patients, other CL sub-types also affect QoL and impact psychosocial distress. Our findings highlight the need for QoL assessment in all CL patients and further examination of disparities noted across demographic groups.

Antimicrobial Efficacy of Methylated Lac Dye, an Anthraquinone Derivative.

A natural red dye which is produced by the tiny insects Kerria lacca while feeding on host trees is popularly known as lac dye. Lac dye is a mixture of at least five closely related pure compounds all being anthraquinone derivatives designated as laccaic acid A, B, C, D and E. Anthraquinones isolated from different natural sources and reported to have potent antimicrobial activity. The lac dye, which is also a mixture of anthraquinone derivatives, is expected to exhibit antifungal and antibacterial activity. Lac dye cannot be used as antibacterial and antifungal agent due to its low water solubility and high polarity. Therefore, it is modified into its methyl derivative to enhance its bio-efficacy. Methylated lac dye is characterized with the help of TLC, UV-Vis spectroscopy and FT-IR, NMR analysis. An in vitro spore germination assay was carried out to evaluate the antifungal efficacy of methylated lac dye against some phytopathogenic fungi which commonly caused a various foliar diseases in crop plants viz., Alternaria solani, Curvularia lunata, Erysiphe pisi, Helminthosporium oryzae and Verticillium sp. Among the tested fungi, Verticillum sp. showed highest sensitivity, which showed 100% inhibition at 750 and 1000 µg/ml as compared to control. However, E. pisi an obligate parasite also showed varied sensitivity but at 1000 µg/ml showed 100% spore germination as compared to control. Methylated lac dye also showed strong antibacterial properties against Ralstonia solanacearum at very low concentration (40 and 50 µg/ml). Hence, lac dye may serve as potent antifungal and antibacterial agent in plant disease management.

Phase 1 Study of Bortezomib, Fludarabine, and Melphalan, With or Without Total Marrow Irradiation, as Allogeneic Hematopoietic Stem Cell Transplant Conditioning for High-risk or Relapsed/Refractory Multiple Myeloma.

OBJECTIVE: We conducted a phase 1 study of a conditioning regimen with or without total marrow irradiation (TMI) before allogeneic hematopoietic stem cell transplantation for patients with high-risk or refractory multiple myeloma. METHODS: Eighteen patients were enrolled on one of 2 strata. Patients with no prior radiation received TMI (900 cGy), fludarabine (FLU), and melphalan (MEL) conditioning, with bortezomib added in the second cohort (stratum I). Patients with prior radiation received FLU, MEL, and bortezomib, without TMI (stratum II). RESULTS: Eight patients were enrolled in the TMI arm (stratum I). One of 3 patients in cohort 1 experienced dose-limiting toxicity (DLT), which led to the expansion to 3 more patients with no DLT. Cohort 2 enrolled only 2 patients due to low accrual, with bortezomib, added at 0.5 mg/m 2 ; neither experienced DLT. Nine patients were enrolled in the non-TMI arm (stratum II). Three patients were enrolled in cohort 1 (bortezomib 0.5 mg/m 2 ) and none experienced DLT. Three were enrolled in cohort 2 (bortezomib 0.7 mg/m 2 ), and 1 experienced DLT; therefore, the cohort expanded to 3 more patients. One more patient experienced DLT. Median overall survival on strata I and II was 44.5 months (95% CI: 1.73-not reached) and 21.6 months (95% CI: 4.1-72.7), respectively. Median progression-free survival on strata I and II was 18.1 months (95% CI: 1.73-not reached) and 8.9 months (95% CI: 2.7-24.4), respectively. CONCLUSION: TMI 900 cGy, FLU, and MEL are considered feasible as conditioning for allogeneic stem cell transplantation and may warrant further investigation due to favorable response rates and survival.

Trace metals and pesticides in water-sediment and associated pollution load indicators of Netravathi-Gurupur estuary, India: Implications on coastal pollution.

Various environmental indicators were used to evaluate the water and sediment quality of the Netravathi-Gurupur estuary, India, for trace metals and pesticide pollution. The descended order of studied metal concentrations (µg/L) in the water was Fe (592.71) > Mn (98.35) > Zn (54.69) > Cu (6.64) > Cd (3.24) > Pb (2.38) > Cr (0.82) and in sediment (mg/kg) was Fe (11,396.53) > Mn (100.61) > Cr (75.41) > Zn (20.04) > Cu (12.77) > Pb (3.46) > Cd (0.02). However, pesticide residues were not detected in this estuarine environment. The various metal indexes categorised the water as uncontaminated, whereas contamination factor, enrichment factor, geo-accumulation index, degree of contamination and pollution load index indicated low to moderate sediment contamination. Multivariate statistics showed that the dominance of natural sources of trace metals with little anthropogenic impact. Improvement in water/sediment quality during the study period might be due to COVID-19 imposed lockdown.

Inhibitory role of copper and silver nanocomposite on important bacterial and fungal pathogens in rice (Oryza sativa).

Rice (Oryza sativa) being among the most important food crops in the world is also susceptible to various bacterial and fungal diseases that are the major stumbling blocks in the way of increased production and productivity. The bacterial leaf blight caused by Xanthomonas oryzae pv. oryzae and the sheath blight disease caused by Rhizoctonia solani are among the most devastating diseases of the rice crop. In spite of the availability of array of chemical control, there are chances of development of resistance. Thus, there is a need for the nanotechnological intervention for management of disease in the form of copper and silver nano-composites. The copper (CuNPs) and silver nanoparticles (AgNPs) were synthesized using green route and characterized using different high throughput techniques, i.e., UV-Vis, FT-IR, DLS, XRD, FE-SEM, TEM. The particle size and zeta potential of synthesized CuNPs and AgNPs were found 273 nm and - 24.2 mV; 95.19 nm and - 25.5 mV respectively. The nanocomposite of CuNPs and AgNPs were prepared having particle size in the range of 375-306 nm with improved stability (zeta potential - 54.7 to - 39.4 mV). The copper and silver nanoparticle composites evaluated against Xanthomonas oryzae pv. oryzae and Rhizoctonia solani were found to have higher antibacterial (inhibition zone 13 mm) and antifungal activities (77%) compared to only the copper nanoparticle (8 mm; 62% respectively). Net house trials of nano-composite formulations against the bacterial blight of rice also corroborated the potential of nanocomposite formulation. In silico studies were carried out selecting two disease-causing proteins, peptide deformylase (Xanthomonas oryzae) and pectate lyase (Rhizoctonia solani) to perform the molecular docking. Interaction studies indicatedthat both of these proteins generated better complex with CuNPs than AgNPs. The study suggested that the copper and silver nano-composites could be used for developing formulations to control these devastating rice diseases.

Study of Drug Delivery Using Purely Organic Macrocyclic Containers-Cucurbit[7]uril and Pillararene.

An impaired immune system is the root of various human ailments provoking the urge to find vehicle-mediated quick delivery of small drug molecules and other vital metabolites to specific tissues and organs. Thus, drug delivery strategies are in need of improvement in therapeutic efficacy. It can be achieved only by increasing the drug-loading capacity, increasing the sustained release of a drug to its target site, easy relocation of drug molecules associated with facile complexation-induced properties of molecular vehicles, and high stimuli-responsive drug administration. Supramolecular drug delivery systems (SDDS) provide a much needed robust yet facile platform for fabricating innovative drug nanocarriers assembled by thermodynamically noncovalent interaction with the tunable framework and above-mentioned properties. Measures of cytotoxicity and biocompatibility are the two main criteria that lie at the root of any promising medicinal applications. This Review features significant advancements in (i) supramolecular host-guest complexation using cucurbit[7]uril (CB[7]), (ii) encapsulation of the drug and its delivery application tailored for CB[7], (iii) self-assembly of supramolecular amphiphiles, (iv) supramolecular guest relay using host-protein nanocavities, (v) pillararene (a unique macrocyclic host)-mediated SDDS for the delivery of smart nanodrugs for siRNA, fluorescent molecules, and insulin for juvenile diabetes. Furthermore, fundamental questions and future hurdles related to smart SDDS based on CB[7] and pillararenes and their future promising breakthrough implementations are also distinctly outlined in this Review.

Rapid and Highly Productive Assembly of a Disulfide Bond in Solid-Phase Peptide Macrocyclization.

Here we report a highly efficient disulfide-driven peptide macrocyclization in 15 min on a solid support using persulfate as a crucial additive in iodine-mediated oxidative cyclization. The method eliminates the side products of classical iodine-mediated peptide cyclization. It is operationally simple and convenient for cyclizing small to lengthier peptides embodying popular cysteine building blocks in a single step.

Geochemical distribution and forms of phosphorus in the surface sediment of Netravathi-Gurupur estuary, southwestern coast of India.

Estuaries are the most productive transition ecosystem and phosphorus (P) plays an important role in these ecosystems. Therefore, in the present study, sequential extraction method was used to determine the abundance of five sediment P fractions (calcium (Ca-P), Iron (FeP), aluminum (AlP), exchangeable (Ex-P) and organic (OrgP) bound P) in Netravathi-Gurupur estuary, India. Total phosphorus (TP) content varied from 435-810 mg/kg (non-monsoon) and 258-699 mg/kg (monsoon). Inorganic P was dominant part. Different P fractions followed similar order (Fe-P > Ca-P > Al-P > Org-P > Ex-P) with respect to seasons. FeP was dominant fraction, indicating probable anthropogenic stress. Sediment may act as source of P as bioavailable P constituted 40-69.2 % of TP. Molar ratio of OC to Org-P in sediment indicated terrestrial sources of organic matter. However, the estimated phosphorus pollution index were lower than one except a few cases indicating less ecological risk with respect to sedimentary TP load.

Normalized difference vegetation index sensor-based nitrogen management in bread wheat (Triticum aestivum L.): Nutrient uptake, use efficiency, and partial nutrient balance.

The present experiment was conducted to assess the impact of fixed and variable doses (using a normalized difference vegetation index-sensor) of nitrogen (N) on wheat yields, nutrient uptake, nitrogen use efficiency, and soil nitrogen balance through the optimization of nitrogen dose. There were 10 treatments based on fixed and variable doses with different splits, and each treatment was replicated three times under a randomized complete block design. The treatments comprised fixed doses of 120 and 150 kg N ha-1 with different splits; variable doses based on sensor readings after application of 60, 90, and 120 kg N ha-1; 225 kg N ha-1 as a nitrogen-rich control; and no application of nitrogen as the absolute control. It was revealed that the application of a basal dose of 60 kg N ha-1 and another 60 kg N ha-1 at the crown root initiation stage followed by a sensor-guided N application significantly improved wheat grain yields and grain nitrogen uptake. However, straw nitrogen uptake was highest in N-rich plots where 225 kg N ha-1was applied. It was found that any curtailment in these doses at basal and crown root initiation stages followed by nitrogen application using a normalized difference vegetation index sensor later could not bring about higher crop yields. On average, wheat crops responded to 152-155 kg N ha-1 in both years of the study. Partial factor productivity along with agronomic and economic nitrogen use efficiency showed a declining trend with an increased rate of N application. Apparent N recovery values were comparable between normalized difference vegetation index sensor-based N application treatments and treatments receiving lesser N doses. Soil N status decreased in all the treatments except the nitrogen-rich strip, where there was a marginal increase in soil N status after the wheat crop harvest in the rotation. Partial nitrogen balance was negative for all the treatments except the control. From these 2-year field trials, it can be concluded that applying a normalized difference vegetation index sensor could be an essential tool for the rational management of fertilizer nitrogen in wheat grown in eastern sub-Himalayan plains.

Leflunomide Confers Rapid Recovery from COVID-19 and is Coupled with Temporal Immunologic Changes.

Background: Vaccines for SARS-CoV-2 have been considerably effective in reducing rates of infection and severe COVID-19. However, many patients, especially those who are immunocompromised due to cancer or other factors, as well as individuals who are unable to receive vaccines or are in resource-poor countries, will continue to be at risk for COVID-19. We describe clinical, therapeutic, and immunologic correlatives in two patients with cancer and severe COVID-19 who were treated with leflunomide after failing to respond to standard-of-care comprising remdesivir and dexamethasone. Both patients had breast cancer and were on therapy for the malignancy. Methods: The protocol is designed with the primary objective to assess the safety and tolerability of leflunomide in treating severe COVID-19 in patients with cancer. Leflunomide dosing consisted of a loading dose of 100 mg daily for the first three days, followed by daily dosing, at the assigned dose level (Dose Level 1: 40 mg, Dose Level -1, 20 mg; Dose Level 2, 60 mg), for an additional 11 days. At defined intervals, serial monitoring of blood samples for toxicity, pharmacokinetics, and immunologic correlative studies were performed, as well as nasopharyngeal swabs for PCR analysis of SARS-CoV-2. Results: Preclinically, leflunomide impaired viral RNA replication, and clinically, it led to a rapid improvement in the two patients discussed herein. Both patients completely recovered, with minimal toxicities; all adverse events experienced were considered unrelated to leflunomide. Single-cell mass-cytometry analysis showed that leflunomide increased levels of CD8+ cytotoxic and terminal effector T cells and decreased naïve and memory B cells. Conclusions: With ongoing COVID-19 transmission and occurrence of breakthrough infections in vaccinated individuals, including patients with cancer, therapeutic agents that target both the virus and host inflammatory response would be helpful despite the availability of currently approved anti-viral agents. Furthermore, from an access to care perspective, especially in resource-limited areas, an inexpensive, readily available, effective drug with existing safety data in humans is relevant in the real-world setting.

Leveraging IFNγ/CD38 regulation to unmask and target leukemia stem cells in acute myelogenous leukemia.

Elimination of drug-resistant leukemia stem cells (LSCs) represents a major challenge to achieve a cure in acute myeloid leukemia (AML). Although AML blasts generally retain high levels of surface CD38 (CD38pos), the presence of CD34 and lack of CD38 expression (CD34posCD38neg) are immunophenotypic features of both LSC-enriched AML blasts and normal hematopoietic stem cells (HSCs). We report that IFN-γ induces CD38 upregulation in LSC-enriched CD34posCD38neg AML blasts, but not in CD34posCD38neg HSCs. To leverage the IFN-γ mediated CD38 up-regulation in LSCs for clinical application, we created a compact, single-chain CD38-CD3-T cell engager (CD38-BIONIC) able to direct T cells against CD38pos blasts. Activated CD4pos and CD8pos T cells not only kill AML blasts but also produce IFNγ, which leads to CD38 expression on CD34posCD38neg LSC-enriched blasts. These cells then become CD38-BIONIC targets. The net result is an immune-mediated killing of both CD38neg and CD38pos AML blasts, which culminates in LSC depletion.

p166, a link between the trypanosome mitochondrial DNA and flagellum, mediates genome segregation.

Kinetoplast DNA (kDNA), the trypanosome mitochondrial genome, is a giant network containing several thousand interlocked DNA rings. Within the mitochondrion, kDNA is condensed into a disk-shaped structure positioned near the flagellar basal body. The disk is linked to the basal body by a remarkable transmembrane filament system named the tripartite attachment complex (TAC). Following kDNA replication, the TAC mediates network segregation, pulling the progeny networks into the daughter cells by their linkage to the basal bodies. So far TAC has been characterized only morphologically with no known protein components. By screening an RNAi library, we discovered p166, a protein localizing between the kDNA and basal body in intact cells and in isolated flagellum-kDNA complexes. RNAi of p166 has only small effects on kDNA replication, but it causes profound defects in network segregation. For example, kDNA replication without segregation causes the networks to grow to enormous size. Thus, p166 is the first reported molecular component of the TAC, and its discovery will facilitate study of kDNA segregation machinery at the molecular level.

The killing of African trypanosomes by ethidium bromide.

Introduced in the 1950s, ethidium bromide (EB) is still used as an anti-trypanosomal drug for African cattle although its mechanism of killing has been unclear and controversial. EB has long been known to cause loss of the mitochondrial genome, named kinetoplast DNA (kDNA), a giant network of interlocked minicircles and maxicircles. However, the existence of viable parasites lacking kDNA (dyskinetoplastic) led many to think that kDNA loss could not be the mechanism of killing. When recent studies indicated that kDNA is indeed essential in bloodstream trypanosomes and that dyskinetoplastic cells survive only if they have a compensating mutation in the nuclear genome, we investigated the effect of EB on kDNA and its replication. We here report some remarkable effects of EB. Using EM and other techniques, we found that binding of EB to network minicircles is low, probably because of their association with proteins that prevent helix unwinding. In contrast, covalently-closed minicircles that had been released from the network for replication bind EB extensively, causing them, after isolation, to become highly supertwisted and to develop regions of left-handed Z-DNA (without EB, these circles are fully relaxed). In vivo, EB causes helix distortion of free minicircles, preventing replication initiation and resulting in kDNA loss and cell death. Unexpectedly, EB also kills dyskinetoplastic trypanosomes, lacking kDNA, by inhibiting nuclear replication. Since the effect on kDNA occurs at a >10-fold lower EB concentration than that on nuclear DNA, we conclude that minicircle replication initiation is likely EB's most vulnerable target, but the effect on nuclear replication may also contribute to cell killing.

Compelling Cyclic Peptide Scaffolds for Antitubercular Action: An Account (2011-21) of the Natural Source.

Natural cyclic peptide scaffolds are indispensable in medicinal chemistry, chemical biology, and drug discovery platforms due to their chemical diversity, structural integrity, proteolytic stability and biocompatibility. Historically, their isolation and profound understanding of target engagement have been identified as lead pharmacophore discovery. Natural cyclic peptides are the largest class of pharmacologically active scaffold, in which most show activity against drug-resistant Mycobacterium tuberculosis (Mtb). Nevertheless, eight recently discovered cyclic peptide scaffolds exhibit promising antitubercular activity among numerous naturally occurring antitubercular peptides, and they are amenable scaffolds to drug development. We examined their biological origin, scaffolds, isolations, chemical synthesis, and reasons for biological actions against Mtb. Understanding these peptide scaffold details will further allow synthetic and medicinal chemists to develop novel peptide therapeutics against tuberculosis-infected deadly diseases. This review emphasizes these cyclic peptides' in vitro and in vivo activity profiles, including their structural and chemical features.

Design and In-silico Screening of Peptide Nucleic Acid (PNA) Inspired Novel Pronucleotide Scaffolds Targeting COVID-19.

INTRODUCTION: The outburst of the novel coronavirus COVID-19, at the end of December 2019 has turned into a pandemic, risking many human lives. The causal agent being SARS-CoV-2, a member of the long-known Coronaviridae family, is a positive-sense single-stranded enveloped virus and closely related to SARS-CoV. It has become the need of the hour to understand the pathophysiology of this disease, so that drugs, vaccines, treatment regimens and plausible therapeutic agents can be produced. METHODS: In this regard, recent studies uncovered the fact that the viral genome of SARS-CoV-2 encodes non-structural proteins like RNA-dependent RNA polymerase (RdRp) which is an important tool for its transcription and replication process. A large number of nucleic acid-based anti-viral drugs are being repurposed for treating COVID-19 targeting RdRp. Few of them are at the advanced stage of clinical trials, including remdesivir. While performing a detailed investigation of the large set of nucleic acid-based drugs, we were surprised to find that the synthetic nucleic acid backbone has been explored very little or rare. RESULTS: We designed scaffolds derived from peptide nucleic acid (PNA) and subjected them to in- -silico screening systematically. These designed molecules have demonstrated excellent binding towards RdRp. Compound 12 was found to possess a similar binding affinity as remdesivir with comparable pharmacokinetics. However, the in-silico toxicity prediction indicates that compound 12 may be a superior molecule which can be explored further due to its excellent safety-profile with LD50 12,000mg/kg as opposed to remdesivir (LD50 =1000mg/kg). CONCLUSION: Compound 12 falls in the safe category of class 6. Synthetic feasibility, equipotent binding and very low toxicity of this peptide nucleic acid-derived compound can make it a leading scaffold to design, synthesize and evaluate many similar compounds for the treatment of COVID-19.