Discovery of low-molecular-weight phenylalanine derivatives as novel HIV capsid modulators with improved antiretroviral activity and metabolic stability.

The HIV capsid (CA) protein is a promising target for anti-AIDS treatment due to its critical involvement in viral replication. Herein, we utilized the well-documented CA inhibitor PF74 as our lead compound and designed a series of low-molecular-weight phenylalanine derivatives. Among them, compound 7t exhibited remarkable antiviral activity with a high selection index (EC50 = 0.040 µM, SI = 2815), surpassing that of PF74 (EC50 = 0.50 µM, SI = 258). Furthermore, when evaluated against the HIV-2 strain, 7t (EC50 = 0.13 µM) demonstrated approximately 14-fold higher potency than that of PF74 (EC50 = 1.76 µM). Insights obtained from surface plasmon resonance (SPR) revealed that 7t exhibited stronger target affinity to the CA hexamer and monomer in comparison to PF74. The potential interactions between 7t and the HIV-1 CA were further elucidated using molecular docking and molecular dynamics simulations, providing a plausible explanation for the enhanced target affinity with 7t over PF74. Moreover, the metabolic stability assay demonstrated that 7t (T1/2 = 77.0 min) significantly outperforms PF74 (T1/2 = 0.7 min) in human liver microsome, exhibiting an improvement factor of 110-fold. In conclusion, 7t emerges as a promising drug candidate warranting further investigation.

Mapping of adult plant recessive resistance to anthracnose in Indian common bean landrace Baspa/KRC 8.

BACKGROUND: The common bean (Phaseolus vulgaris) has become the food of choice owing to its wealthy nutritional profile, leading to a considerable increase in its cultivation worldwide. However, anthracnose has been a major impediment to production and productivity, as elite bean cultivars are vulnerable to this disease. To overcome barriers in crop production, scientists worldwide are working towards enhancing the genetic diversity of crops. One way to achieve this is by introducing novel genes from related crops, including landraces like KRC 8. This particular landrace, found in the North Western Himalayan region, has shown adult plant resistance against anthracnose and also possesses a recessive resistance gene. METHODS AND RESULTS: In this study, a population of 179 F2:9 RIL individuals (Jawala × KRC 8) was evaluated at both phenotypic and genotypic levels using over 830 diverse molecular markers to map the resistance gene present in KRC 8. We have successfully mapped a resistance gene to chromosome Pv01 using four SSR markers, namely IAC 238, IAC 235, IAC 259, and BM 146. The marker IAC 238 is closely linked to the gene with a distance of 0.29 cM, while the other markers flank the recessive resistance gene at 10.87 cM (IAC 259), 17.80 cM (BM 146), and 25.22 cM (IAC 235). Previously, a single recessive anthracnose resistance gene (co-8) has been reported in the common bean accession AB 136. However, when we performed PCR amplification with our tightly linked marker IAC 238, we got different amplicons in AB 136 and KRC 8. Interestingly, the susceptible cultivar Jawala produced the same amplicon as AB 136. This observation indicated that the recessive gene present in KRC 8 is different from co-8. As the gene is located far away from the Co-1 locus, we suggest naming the recessive gene co-Indb/co-19. Fine mapping of co-Indb in KRC 8 may provide new insights into the cloning and characterization of this recessive gene so that it can be incorporated into future bean improvement programs. Further, the tightly linked marker IAC 238 can be utilized in marker assisted introgression in future bean breeding programs. CONCLUSION: The novel co-Indb gene present in Himalayan landrace KRC 8, showing adult plant resistance against common bean anthracnose, is independent from all the resistance genes previously located on chromosome Pv01.

Increased taxes and regulation of Indian cigarillos (bidi) industry: Effects on revenue and years of life lost.

INTRODUCTION: Indian cigarillos (bidi) are low-cost alternatives to cigarettes with only 22% imposed taxes, and turnover of upto INR 4 million per annum exempted from taxation. This paper estimates revenue implications and potential loss of life years (YLLs) averted, if bidi industry is subjected to increased regulations and taxation. METHODS: Revenue estimated at 10% increased regulation and 100% regulation were calculated, followed by estimates at taxes equivalent to cigarettes and World Health Organization - Framework Convention on Tobacco Control (WHO-FCTC) recommendation. Price elasticity was considered to assess demand. Price change in separate fractions (previously regulated and unregulated) were calculated to obtain potential YLLs averted. RESULTS: Current revenue of USD 59.25 million is projected to increase to USD 179.25 million with 695,159 averted YLLs at cigarette equivalent taxes and 10% increased regulation; USD 639.38 million with 4,527,597 averted YLLs with 100% regulation; USD 54.75 million, at WHO recommended taxes with 2,233,740 YLLs averted at 10% increased regulation, and 10,486,192 YLLs at 100% regulation. CONCLUSION: Proposed estimates are inline with WHO recommendations as they consider price elasticity and suggest substantial increase in revenue, while averting YLLs. A national action is needed to drive the policy decisions towards increased regulation and taxation and revision of India's tobacco control legislation. IMPLICATIONS: Our study presented empirical evidence of how the currently underutilized tool of taxation, as proposed in the WHO-FCTC, can be utilized to decrease bidi smoking prevalence and save measurable life years while generating government revenue simultaneously. While the revenue statistics counter the misleading tobacco industry narratives, the projected reduction in mortality will be seen as an irrefutable driving force for policy reforms, targeted at strategic increase in regulation and taxation of the traditional Indian cigarillos industry.

Incidence, Risk Factors, Characteristics, and Outcome of Chronic Graft Versus Host Disease in Children Undergoing Haploidentical Peripheral Blood Stem Cell Transplant With Post-transplant Cyclophosphamide.

AIM: Chronic graft versus host disease (cGVHD) is a major cause of morbidity postallogeneic peripheral blood stem cell transplant (PBSCT). There is paucity of literature describing incidence, risk factors, characteristics, and outcome of cGVHD in children undergoing haploidentical PBSCT with post-transplant cyclophosphamide (PTCy). Here, we describe our experience from our center regarding the same. METHODS: All children who underwent haploidentical PBSCT with PTCy between January 2016 and December 2021 at our center and survived beyond day+100 post-transplant were included in this retrospective study. Conditioning regimens used were: Thiotepa-Fludarabine-Cyclophosphamide with 2 Gy single fraction total body irradiation, Thiotepa-Busulfan-Fludarabine, Fludarabine-total body irradiation and Fludarabine-Melphalan. Peripheral blood was used as stem cell source in all patients. GVHD prophylaxis was PTCy 50 mg/kg on day +3 and +4, Mycophenolate mofetil and Calcineurin inhibitors. Clinical and laboratory data was electronically retrieved and analyzed based on National Institute of Health Consensus Criteria-2014 at regular intervals. Impact of various patient, donor, and transplant-related factors on development of cGVHD were analyzed. Incidence of relapse, event free survival (EFS) and overall survival (OS) were calculated and compared between cGVHD and no cGVHD groups. Patients with rejection were excluded from risk factor analysis for cGVHD but were considered for survival analysis. RESULTS: Fifty-one children included in this study. Median age of transplant of our cohort was 7.5 years with male:female=1.6:1. Eight patients had rejection with autologous recovery. History of acute GVHD (aGVHD) was present in 15/51 (Grade III to IV in 7/51). cGVHD developed in 19/51 patients (mild-9/51, moderate-6/51, and severe-4/51). Skin was the most common organ involved (100%) followed by gastrointestinal tract (47.4%), liver (36.8%), eyes (21%), lungs (21%), mouth (15.7%), and joints (5.2%). Advanced donor age (>30 y) and previous aGVHD were found to be significantly associated with increased risk of developing cGVHD. At last follow-up, complete response and partial response of cGVHD was seen in 6/19 and 4/19 patients, respectively. Overall mortality was 15/51 (cause of mortality was relapse of cancer 8/15, cGVHD-3/15, other 4/15). EFS and OS of full cohort was 55% and 70.6%, respectively. Compared with patients without cGVHD, patients with cGVHD demonstrated a lower relapse (18.2% vs. 40%, P =0.2333), higher EFS (68.4% vs. 53.1%, P =0.283), and higher OS (73.7% vs. 68.8%, P =0.708). CONCLUSION: Incidence of cGVHD was high in children undergoing haploidentical PBSCT with PTCy. Other than PBSC graft source; donor age and previous aGVHD were the risks factors for development of cGVHD. Patients with cGVHD had lower incidence of relapse translating into better survival but this difference was not statistically significant.

Quality Assessment of Interactive Mobile Application - Maternal and Infant Care for Tribal Birth Attendants.

Digital health interventions can overcome geographical barriers and prepare health-care providers for better health outcomes in rural and remote tribal areas, however, it has not been explored among traditional birth attendants (TBAs). A mobile application, "maternal and infant care" (MAI) for capacity building of tribal birth attendants was developed and its quality was evaluated using the Mobile Application Rating Scale for user's interest in and satisfaction with the esthetics, information, and functionality. Thirteen Android user TBAs with the MAI application were piloted with the MARS checklist. Engagement, functionality, esthetics, and information quality; and one subjective quality scale having 29 items were used. The application was found to be entertaining excellent rating (mean score ± standard deviation) (4.00 ± 0.58), and scored high on performance (3.77 ± 0.93); layout design (3.85 ± 0.90); subjective quality (4.23 ± 0.93), however, scored minimum on interest; gestural design; visual appeal, etc. MAI is a user-friendly, culturally acceptable Android app that can be used for the capacity building of frontline workers.

Estimating the weight of consumed tobacco product waste in various Indian states: a novel method to assess the potential burden of tobacco product waste.

INTRODUCTION: The direct morbidity and mortality caused by tobacco are well documented, but such products also contribute to a range of environmental pollutants resulting from tobacco product waste. No previous studies have yet quantified tobacco product waste in a low-income and middle-income country (LMIC). This study estimates the potential annual waste generated due to consumption of smoked and smokeless tobacco products in India and its states. METHODOLOGY: We systematically collected samples of smoked and smokeless tobacco products from 33 districts of 17 Indian states/union territories. Stratified weights of plastic, paper, foil and filter packaging components, and gross empty package weights were recorded. Prevalence of smoking and smokeless tobacco use at national and state-level estimates was derived from the Global Adult Tobacco Survey (2016-2017) to quantify waste potentially generated by tobacco products. RESULTS: We included 222 brands of tobacco products (70 cigarette, 94 bidi and 58 smokeless tobacco brands) in the final analysis. A total of 170 331 (±29 332) tonnes of waste was estimated to be generated annually, out of which 43.2% was plastic, 3.6% was foil and 0.8% was filter. Two-thirds of the overall waste was contributed by smokeless products alone. Maximum waste was generated in Uttar Pradesh (20.9%; 35 723.7±6151.6 tonnes), Maharashtra (8.9%; 15 116.84±2603.12 tonnes) and West Bengal (8.6%; 14 636.32±2520.37 tonnes). CONCLUSION: This study provides first of its kind national-level evidence on the types (plastic, paper, foil and filter) and quantity of waste potentially generated by use of tobacco products in India. Similar studies from other LMICs can serve to raise consciousness about many negative environmental impacts of tobacco products and need for policies to address them.

Effect of prey density on the performance of Eupeodes corollae and its predation rate against the cabbage aphid, Brevicorynae brassicae (L.).

Eupeodes corollae (F.) (Diptera: Syrphidae) is the most abundant syrphid fly which is distributed worldwide and is the sole predator of aphids. Therefore, the present study was conducted to evaluate the predation rate and functional response of E. corollae against the cabbage aphid, Brevicoryne brassicae (L.). The experiment was carried out under laboratory conditions at 25 ± 2°C with 60-70% relative humidity. The results revealed that age-specific net predation rate (qx) increased after the 4th day and a peak was recorded on the 10th day of pivotal age in the third larval instar. The stable host kill rate and finite host kill rate of E. corollae were 18.63 and 21.07, respectively, against the B. brassicae and predicted that a mean of 20.78 aphids was needed for E. corollae to produce one offspring. A negative linear coefficient (P < 0) indicated the type II functional response for all larval instars of E. corollae against the B. brassicae. At higher prey density, the prey consumption was significantly at par with second and third instar larvae of E. corollae as the prey consumption was increased with increasing the prey density, which then decreased after attaining the upper asymptote (76.40 and 81.40% consumption, respectively). The Roger's predator random equation for type II functional response was fitted to estimate attack rate (a) and handling time (Th). The maximum prey consumption was recorded for third instar of E. corollae with a higher attack rate (0.336 h-1) and lower handling time (0.514 h) against B. brassicae, followed by the second and first instar. Thus, it is concluded that the third larval instar of E. corollae was the voracious feeder and used as an efficient biocontrol agent in the IPM programme.

A Survey Study on Knowledge and Attitude Toward the Ethics Committee and Research Ethical Practices Among Researchers From Kuwait.

The integrity of research findings and the safety of participants who voluntarily consent to participate in research studies must be assured through ethical approaches. Additionally, ethical guidelines and the ethics committee protect participants from unfair practices by the research team. Therefore, this study aims to assess the knowledge and attitudes toward the ethics committee and research ethical practices among the researchers of a diabetes institute in Kuwait. An anonymous survey was conducted through an online questionnaire using Microsoft Forms. The study had a response rate of 86%. Among the 55 participants in this study, 43 (78%) had ethics training. Researchers involved in more than four research projects were shown to have a much higher awareness of the ethics committee and its role than researchers involved in no projects. Approximately 90% of researchers had training in research ethics and were knowledgeable about informed consent forms and assent, as well as additional protections for vulnerable populations. Ninety-eight percent of respondents were of the view that an ethics committee was necessary. Our study concluded that most of the researchers at the institute were aware of the role of the ethics committee, and ethical principles. However, we recommend that continuous and customized training on research ethics should be provided.

Is maternal anemia among tribal women being neglected? A study from Southern Rajasthan.

Poor birth outcomes have been linked to maternal anemia. Tribal women are at higher risk of malnutrition and disease due to sociocultural barriers and poor educational status. The data on the prevalence of maternal anemia and its associated factors among pregnant tribal women are limited. A community-based cross-sectional study was conducted among 429 pregnant tribal women for maternal anemia from August 2021 to June 2022. A structured questionnaire was employed to collect sociodemographic data. The prevalence of anemia was 85.7%, with a mean hemoglobin level of 9.21 ± 1.3 g/dL. On applying WHO 2011 anemia criteria for pregnant women, 25.0% had mild anemia, 73.4% had moderate anemia, and 1.6% had severe anemia. The significant factors associated with anemic condition were household condition, monthly income, and husband's occupation. The higher prevalence of anemia among pregnant tribal women is alarming that necessitates a rethinking of health infrastructure and outreach in tribal dominant areas.

Cloning and in silico characterization of cinnamyl alcohol dehydrogenase gene involved in lignification of Tall fescue (Festuca arundinacea Schreb.).

Tall fescue, a promising temperate forage grass of Himalayan region, possesses extraordinary property of rapid growth with high biomass production, but its poor digestibility due to higher lignin content limits its utilization in livestock feeding. The lignification in Tall fescue is under the control of enzymatic cascade of different regulatory enzymes. Cinnamyl alcohol dehydrogenase (CAD) is a crucial regulatory enzyme that catalyzes the last step of monolignol biosynthesis and is a potential candidate for altering the content and types of lignin, and hence increasing the digestibility of fodder crops. Hence, the present investigation was conducted on isolation, cloning and characterization of CAD gene from Tall fescue. Isolation and amplification of CAD gene resulted in an amplicon of 1521 bp. The CAD gene sequence was submitted to NCBI database with an accession number MW442831. Translation of the CAD gene sequence exhibited an ORF of 361 amino acids. The deduced CAD protein was predicted to be hydrophobic, acidic and thermally stable with molecular formula C1712H2734N460O520S23, molecular mass of 38.82 kDa, theoretical pI of 5.60 and 3 strong transmembrane helices. The CAD protein was predicted to have a dimer forming behavior with putative NAD(P) binding site between amino acids 48 and 301, putative substrate-binding site between amino acids 48 and 301, catalytic zinc-binding site between amino acids 48 and 164 and structural zinc-binding site between amino acid residue 101 and 115. A conserved 189GLGGVG194 motif is the binding site for NADP(H). The conserved motif pattern of CAD's zinc catalytic center was found to be 69GHEVVGEV(X)EVG(X)2V83. The zinc-binding site was found to be conserved between amino acid 89 and 115 and was found to be 89G(X)2VG(X)G(X)2VGXC(X)2C(X)2C(X)5QYC115. The deciphered sequence and putative protein information might be useful in subsequent research in lignin bioengineering for enhanced digestibility, biomass conversion as well as impact of lignin on cell wall mechanics.

Discovery of novel 1,2,4-triazole phenylalanine derivatives targeting an unexplored region within the interprotomer pocket of the HIV capsid protein.

Human immunodeficiency virus (HIV) capsid (CA) protein is a promising target for developing novel anti-HIV drugs. Starting from highly anticipated CA inhibitors PF-74, we used scaffold hopping strategy to design a series of novel 1,2,4-triazole phenylalanine derivatives by targeting an unexplored region composed of residues 106-109 in HIV-1 CA hexamer. Compound d19 displayed excellent antiretroviral potency against HIV-1 and HIV-2 strains with EC50 values of 0.59 and 2.69 µM, respectively. Additionally, we show via surface plasmon resonance (SPR) spectrometry that d19 preferentially interacts with the hexameric form of CA, with a significantly improved hexamer/monomer specificity ratio (ratio = 59) than PF-74 (ratio = 21). Moreover, we show via SPR that d19 competes with CPSF-6 for binding to CA hexamers with IC50 value of 33.4 nM. Like PF-74, d19 inhibits the replication of HIV-1 NL4.3 pseudo typed virus in both early and late stages. In addition, molecular docking and molecular dynamics simulations provide binding mode information of d19 to HIV-1 CA and rationale for improved affinity and potency over PF-74. Overall, the lead compound d19 displays a distinct chemotype form PF-74, improved CA affinity, and anti-HIV potency.

Multi-targeting approach for nsp3, nsp9, nsp12 and nsp15 proteins of SARS-CoV-2 by Diosmin as illustrated by molecular docking and molecular dynamics simulation methodologies.

Novel coronavirus SARS-CoV-2continues tospread rapidly worldwide and causing serious health and economic loss. In the absence of any effective treatment, various in-silico approaches are being explored towards the therapeutic discovery against COVID-19. Targeting multiple key enzymes of SARS-CoV-2 with a single potential drug could be an important in-silico strategy to tackle the therapeutic emergency. A number of Food and Drug Administration (FDA) approved drugs entered into clinical stages were originated from multi-target approaches with an increased rate, 16-21% between 2015 and 2017. In this study, we selected an FDA-approved library (Prestwick Chemical Library of 1520 compounds) and implemented in-silico virtual screening against multiple protein targets of SARS-CoV-2 on the Glide module of Schrödinger software (release 2020-1). Compounds were analyzed for their docking scores and the top-ranked against each targeted protein were further subjected to Molecular Dynamics (MD) simulations to assess the binding stability of ligand-protein complexes. A multi-targeting approach was optimized that enabled the analysis of several compounds' binding efficiency with more than one protein targets. It was demonstrated that Diosmin (6) showed the highest binding affinity towards multiple targets with binding free energy (kcal/mol) values of -63.39 (nsp3); -62.89 (nsp9); -31.23 (nsp12); and -65.58 (nsp15). Therefore, our results suggests that Diosmin (6) possesses multi-targeting capability, a potent inhibitor of various non-structural proteins of SARS-CoV-2, and thus it deserves further validation experiments before using as a therapeutic against COVID-19 disease.

Recalibrating the Non-Communicable Diseases risk prediction tools for the rural population of Western India.

BACKGROUND: The aim of the present study was to recalibrate the effectiveness of Indian Diabetes Risk Score (IDRS) and Community-Based Assessment Checklist (CBAC) by opportunistic screening of Diabetes Mellitus (DM) and Hypertension (HT) among the people attending health centres, and estimating the risk of fatal and non-fatal Cardio-Vascular Diseases (CVDs) among them using WHO/ISH charts. METHODS: All the people aged ≥ 30 years attending the health centers were screened for DM and HT. Weight, height, waist circumference, and hip circumferences were measured, and BMI and Waist-Hip Ratio (WHR) were calculated. Risk categorization of all participants was done using IDRS, CBAC, and WHO/ISH risk prediction charts. Individuals diagnosed with DM or HT were started on treatment. The data was recorded using Epicollect5 and was analyzed using SPSS v.23 and MedCalc v.19.8. ROC curves were plotted for DM and HT with the IDRS, CBAC score, and anthropometric parameters. Sensitivity (SN), specificity (SP), Positive Predictive Value (PPV), Negative Predictive Value (NPV), Accuracy and Youden's index were calculated for different cut-offs of IDRS and CBAC scores. RESULTS: A total of 942 participants were included for the screening, out of them, 9.2% (95% CI: 7.45-11.31) were diagnosed with DM for the first time. Hypertension was detected among 25.7% (95% CI: 22.9-28.5) of the participants. A total of 447 (47.3%) participants were found with IDRS score ≥ 60, and 276 (29.3%) with CBAC score > 4. As much as 26.1% were at moderate to higher risk (≥ 10%) of developing CVDs. Area Under the Curve (AUC) for IDRS in predicting DM was 0.64 (0.58-0.70), with 67.1% SN and 55.2% SP (Youden's Index 0.22). While the AUC for CBAC was 0.59 (0.53-0.65). For hypertension both the AUCs were 0.66 (0.62-0.71) and 0.63 (0.59-0.67), respectively. CONCLUSIONS: IDRS was found to have the maximum AUC and sensitivity thereby demonstrating its usefulness as compared to other tools for screening of both diabetes and hypertension. It thus has the potential to expose the hidden NCD iceberg. Hence, we propose IDRS as a useful tool in screening of Diabetes and Hypertension in rural India.

Alkaline Stable Anion Exchange Membranes Based on Cross-Linked Poly(arylene ether sulfone) Bearing Dual Quaternary Piperidines for Enhanced Anion Conductivity at Low Water Uptake.

Alkaline stable anion exchange membranes based on the cross-linked poly(arylene ether sulfone) grafted with dual quaternary piperidine (XPAES-DP) units were synthesized. The chemical structure of the synthesized PAES-DP was validated using 1H-NMR and FT-IR spectroscopy. The physicochemical, thermal, and mechanical properties of XPAES-DP membranes were compared with those of two linear PAES based membranes grafted with single piperidine (PAES-P) unit and conventional trimethyl amine (PAES-TM). XPAES-DP membrane showed the ionic conductivity of 0.021 S cm-1 at 40 °C which was much higher than that of PAES-P and PAES-TM because of the possession of more quaternary ammonium groups in the cross-linked structure. This cross-linked structure of the XPAES-DP membrane resulted in a higher tensile strength of 18.11 MPa than that of PAES-P, 17.09 MPa. In addition, as the XPAES-DP membrane shows consistency in the ionic conductivity even after 96 h in 3 M KOH solution with a minor change, its chemical stability was assured for the application of anion exchange membrane fuel cell. The single-cell assembled with XPAES-DP membrane displayed a power density of 109 mWcm-2 at 80 °C under 100% relative humidity.

Design, Synthesis and Structure-Activity Relationships of Phenylalanine-Containing Peptidomimetics as Novel HIV-1 Capsid Binders Based on Ugi Four-Component Reaction.

As a key structural protein, HIV capsid (CA) protein plays multiple roles in the HIV life cycle, and is considered a promising target for anti-HIV treatment. Based on the structural information of CA modulator PF-74 bound to HIV-1 CA hexamer, 18 novel phenylalanine derivatives were synthesized via the Ugi four-component reaction. In vitro anti-HIV activity assays showed that most compounds exhibited low-micromolar-inhibitory potency against HIV. Among them, compound I-19 exhibited the best anti-HIV-1 activity (EC50 = 2.53 ± 0.84 µM, CC50 = 107.61 ± 27.43 µM). In addition, I-14 displayed excellent HIV-2 inhibitory activity (EC50 = 2.30 ± 0.11 µM, CC50 > 189.32 µM) with relatively low cytotoxicity, being more potent than that of the approved drug nevirapine (EC50 > 15.02 µM, CC50 > 15.2 µM). Additionally, surface plasmon resonance (SPR) binding assays demonstrated direct binding to the HIV CA protein. Moreover, molecular docking and molecular dynamics simulations provided additional information on the binding mode of I-19 to HIV-1 CA. In summary, we further explored the structure­activity relationships (SARs) and selectivity of anti-HIV-1/HIV-2 of PF-74 derivatives, which is conducive to discovering efficient anti-HIV drugs.

Design, synthesis, and antiviral activity of phenylalanine derivatives as HIV-1 capsid inhibitors.

The HIV-1 Capsid (CA) is considered as a promising target for the development of potent antiviral drugs, due to its multiple roles during the viral life cycle. Herein, we report the design, synthesis, and antiviral activity evaluation of series of novel phenylalanine derivatives as HIV-1 CA protein inhibitors. Among them, 4-methoxy-N-methylaniline substituted phenylalanine (II-13c) and indolin-5-amine substituted phenylalanine (V-25i) displayed exceptional anti-HIV-1 activity with the EC50 value of 5.14 and 2.57 µM respectively, which is slightly weaker than that of lead compound PF-74 (EC50 = 0.42 µM). Besides, surface plasmon resonance (SPR) binding assay demonstrated II-13c and V-25i prefer to combine with CA hexamer rather than monomer, which is similar to PF-74. Subsequently, molecular dynamics simulation (MD) revealed potential interactions between representative compounds with HIV-1 CA hexamer. Overall, this work laid a solid foundation for further structural optimization to discover novel promising HIV-1 CA inhibitors.

Searching Anti-Zika Virus Activity in 1H-1,2,3-Triazole Based Compounds.

Zika virus (ZIKV) is a mosquito-borne virus belonging to the Flaviviridae family and is responsible for an exanthematous disease and severe neurological manifestations, such as microcephaly and Guillain-Barré syndrome. ZIKV has a single strand positive-sense RNA genome that is translated into structural and non-structural (NS) proteins. Although it has become endemic in most parts of the tropical world, Zika still does not have a specific treatment. Thus, in this work we evaluate the cytotoxicity and antiviral activities of 14 hybrid compounds formed by 1H-1,2,3-triazole, naphthoquinone and phthalimide groups. Most compounds showed low cytotoxicity to epithelial cells, specially the 3b compound. After screening with all compounds, 4b was the most active against ZIKV in the post-infection test, obtaining a 50% inhibition concentration (IC50) of 146.0 µM and SI of 2.3. There were no significant results for the pre-treatment test. According to the molecular docking compound, 4b was suggested with significant binding affinity for the NS5 RdRp protein target, which was further corroborated by molecular dynamic simulation studies.

Discovery of New Hydroxyethylamine Analogs against 3CLpro Protein Target of SARS-CoV-2: Molecular Docking, Molecular Dynamics Simulation, and Structure-Activity Relationship Studies.

The novel coronavirus, SARS-CoV-2, has caused a recent pandemic called COVID-19 and a severe health threat around the world. In the current situation, the virus is rapidly spreading worldwide, and the discovery of a vaccine and potential therapeutics are critically essential. The crystal structure for the main protease (Mpro) of SARS-CoV-2, 3-chymotrypsin-like cysteine protease (3CLpro), was recently made available and is considerably similar to the previously reported SARS-CoV. Due to its essentiality in viral replication, it represents a potential drug target. Herein, a computer-aided drug design (CADD) approach was implemented for the initial screening of 13 approved antiviral drugs. Molecular docking of 13 antivirals against the 3-chymotrypsin-like cysteine protease (3CLpro) enzyme was accomplished, and indinavir was described as a lead drug with a docking score of -8.824 and a XP Gscore of -9.466 kcal/mol. Indinavir possesses an important pharmacophore, hydroxyethylamine (HEA), and thus, a new library of HEA compounds (>2500) was subjected to virtual screening that led to 25 hits with a docking score more than indinavir. Exclusively, compound 16 with a docking score of -8.955 adhered to drug-like parameters, and the structure-activity relationship (SAR) analysis was demonstrated to highlight the importance of chemical scaffolds therein. Molecular dynamics (MD) simulation analysis performed at 100 ns supported the stability of 16 within the binding pocket. Largely, our results supported that this novel compound 16 binds with domains I and II, and the domain II-III linker of the 3CLpro protein, suggesting its suitability as a strong candidate for therapeutic discovery against COVID-19.

Intercalated Poly (2-Acrylamido-2-methyl-1-propanesulfonic Acid) into Sulfonated Poly (1,4-Phenylene ether-ether-sulfone) Based Proton Exchange Membrane: Improved Ionic Conductivity.

A series of hybrid proton exchange membranes were synthesized via in situ polymerization of poly (2-acrylamido-2-methyl-1-propanesulfonic acid) PMPS with sulfonated poly (1,4-phenylene ether-ether-sulfone) (SPEES). The insertion of poly (2-acrylamido-2-methyl-1-propanesulfonic acid) PMPS, between the rigid skeleton of SPEES plays a reinforcing role to enhance the ionic conductivity. The synthesized polymer was chemically characterized by fourier-transform infrared spectroscopy (FT-IR) and nuclear magnetic resonance 1H NMR spectroscopy to demonstrate the successful grafting of PMPS with the pendent polymer chain of SPEES. A variety of physicochemical properties were also investigated such as ion exchange capacity (IEC), proton conductivity, water uptake and swelling ratio to characterize the suitability of the formed polymer for various electrochemical applications. SP-PMPS-03, having the highest concentration of all PMPS, shows excellent proton conductivity of 0.089 S cm-1 at 80 °C which is much higher than SPEES which is ~0.049 S cm-1. Optimum water uptake and swelling ratio with high conductivity is mainly attributed to a less ordered arrangement polymer chain with high density of the functional group to facilitate ionic transport. The residual weight was 93.35, 92.44 and 89.56%, for SP-PMPS-01, 02 and 03, respectively, in tests with Fenton's reagent after 24 h. In support of all above properties a good chemical and thermal stability was also achieved by SP-PMPS-03, owing to the durability for electrochemical application.

Prevalence and factors associated with effective helmet use among motorcyclists in Mysuru City of Southern India.

BACKGROUND: Helmet use reduces the risk and severity of head injury and death due to road traffic crash among motorcyclists. The protective efficacy of different types of helmets varies. Wearing firmly fastened full-face helmet termed as effective helmet use provides greatest protection. This study estimates the prevalence and factors associated with effective helmet use among motorcyclists in Mysuru, a tier II city in Southern India. METHODS: Cross-sectional road side observational study of 3499 motorcyclists (2134 motorcycle riders and 1365 pillion riders) at four traffic intersections was done followed by interview of random sample of 129 of the above riders. Effective helmet use proportion and effective helmet use per 100 person-minute of observation was calculated. Multivariate logistic regression analysis was done to identify factors associated with effective helmet use. RESULTS: Prevalence of effective helmet use was 28 per 100 riders and 19.5 per 100 person-minute of observation in traffic intersections. Prevalence rates of effective helmet use was higher among riders (34.5% vs pillion riders 18.1%), female riders (51.3% vs male riders 26.8%), and male pillion riders (30.5% vs female pillion riders 13.7%). Riders commuting for work and school and those ever stopped by the police in the past 3 months had significantly higher odds of effective helmet use. CONCLUSION: Despite helmet use being compulsory by law for motorcyclists, the effective helmet use was low in Mysore. Strict enforcement and frequent checks by the police are necessary to increase the effective helmet use.