HIV Protease Inhibitors Research Articles

Inhibition of HIV-1 Protease by a Boronic Acid with High Oxidative Stability.

HIV-1 protease is an important target for pharmaceutical intervention in HIV infection. Extensive structure-based drug design led to darunavir becoming a key chemotherapeutic agent. We replaced the aniline group of darunavir with a benzoxaborolone to form BOL-darunavir. This analogue has the same potency as darunavir as an inhibitor of catalysis by wild-type HIV-1 protease and, unlike darunavir, does not lose potency as an inhibitor of the common D30N variant. Moreover, BOL-darunavir is much more stable to oxidation than is a simple phenylboronic acid analogue of darunavir. X-ray crystallography revealed an extensive network of hydrogen bonds between the enzyme and benzoxaborolone moiety, including a novel direct hydrogen bond from a main-chain nitrogen to the carbonyl oxygen of the benzoxaborolone moiety that displaces a water molecule. These data highlight the utility of benzoxaborolone as a pharmacophore.

Plasmodium DDI1 is a potential therapeutic target and important chromatin-associated protein

DNA damage inducible 1 protein (DDI1) is involved in a variety of cellular processes including proteasomal degradation of specific proteins. All DDI1 proteins contain a ubiquitin-like (UBL) domain and a retroviral protease (RVP) domain. Some DDI1 proteins also contain a ubiquitin-associated (UBA) domain. The three domains confer distinct activities to DDI1 proteins. The presence of a RVP domain makes DDI1 a potential target of HIV protease inhibitors, which also block the development of malaria parasites. Hence, we investigated the DDI1 of malaria parasites to identify its roles during parasite development and potential as a therapeutic target. DDI1 proteins of Plasmodium and other apicomplexan parasites share the UBL-RVP domain architecture, and some also contain the UBA domain. Plasmodium DDI1 is expressed across all the major life cycle stages and is important for parasite survival, as conditional depletion of DDI1 protein in the mouse malaria parasite Plasmodium berghei and the human malaria parasite Plasmodium falciparum compromised parasite development. Infection of mice with DDI1 knock-down P. berghei was self-limiting and protected the recovered mice from subsequent infection with homologous as well as heterologous parasites, indicating the potential of DDI1 knock-down parasites as a whole organism vaccine. Plasmodium falciparum DDI1 (PfDDI1) is associated with chromatin and DNA-protein crosslinks. PfDDI1-depleted parasites accumulated DNA-protein crosslinks and showed enhanced susceptibility to DNA-damaging chemicals, indicating a role of PfDDI1 in removal of DNA-protein crosslinks. Knock-down of PfDDI1 increased susceptibility to the retroviral protease inhibitor lopinavir and antimalarial artemisinin, which suggests that simultaneous inhibition of DDI1 could potentiate antimalarial activity of these drugs. As DDI1 knock-down parasites confer protective immunity and it could be a target of HIV protease inhibitors, Plasmodium DDI1 is a potential therapeutic target for malaria control.

The CNC-family transcription factor Nrf3 coordinates the melanogenesis cascade through macropinocytosis and autophagy regulation

Melanin is a pigment produced from the amino acid L-tyrosine in melanosomes. The CNC-family transcription factor Nrf3 is expressed in the basal layer of the epidermis, where melanocytes reside, but its melanogenic function is unclear. Here, we show that Nrf3 regulates macropinocytosis and autophagy to coordinate melanogenesis cascade. In response to an exogenous inducer of melanin production, forskolin, Nrf3 upregulates the core melanogenic gene circuit, which includes Mitf, Tyr, Tyrp1, Pmel, and Oca2. Furthermore, Nrf3 induces the gene expression of Cln3, an autophagosome-related factor, for melanin precursor uptake by macropinocytosis. Ulk2 and Gabarapl2 are also identified as Nrf3-target autophagosome-related genes for melanosome formation. In parallel, Nrf3 prompts autolysosomal melanosome degradation for melanocyte survival. An endogenous melanogenic inducer αMSH also activates Nrf3-mediated melanin production, whereas it is suppressed by an HIV-1 protease inhibitor, nelfinavir. These findings indicate the significant role of Nrf3 in the melanogenesis and the anti-melanogenic potential of nelfinavir.

Prevalence and dynamics of NAFLD-associated fibrosis in people living with HIV in Vienna from first presentation to last follow-up.

Non-alcoholic fatty liver disease (NAFLD) is frequent in people living with HIV (PLWH) and may be aggravated by metabolic comorbidities and antiretroviral therapy (ART)-associated adverse effects. We retrospectively assessed epidemiological, clinical and laboratory parameters and ART regimens at HIV diagnosis (BL) and at last follow-up (FU) in 1458 PLWH without viral hepatitis coinfection attending our HIV clinic in 2014-2016. Fibrosis was non-invasively assessed by the NAFLD fibrosis score (NFS). The median age of subjects was 37.8years, 77.4% were male and 67.2% on ART, median CD4+ count was 356.0cells/µL. At BL, 503 (34.5%) and 20 (1.4%) PLWH had dyslipidemia and diabetes, respectively. According to the NFS 16 (1.3%) showed advanced fibrosis (NFS ≥ 0.676), among which 1 (6.3%) had diabetes, 7 (43.8%) had dyslipidemia, and 5 (31.3%) were on HIV-protease inhibitors (PI). In addition, 191(15.1%) had intermediate NFS results, while fibrosis was ruled out (NFS ≤ 1.455) in 1065 (83.7%) PLWH. After amedian follow-up of 6.3years, 590 (42.8%) had dyslipidemia and 61 (4.4%) had diabetes. Also, 21 (1.6%) showed advanced fibrosis, of which 10 (47.6%) had diabetes, 4 (19.0%) had dyslipidemia, and 9 (42.9%) were on PI-based ART, 223 (17.4%) had intermediate NFS results, while 1039 (81.0%) showed no fibrosis. During FU, advanced NAFLD fibrosis occurred in 1.3-1.6% of PLWH. Dyslipidemia, diabetes, and PI-based ART were associated with advanced NAFLD fibrosis. Prospective investigations of NAFLD severity and risk factors in PLWH are warranted.

A Comparative Study for the Accuracy of Three Molecular Docking Programs Using HIV-1 Protease Inhibitors as a Model

Flexible molecular docking is a computational method of structure-based drug design to evaluate binding interactions between receptor and ligand and identify the ligand conformation within the receptor pocket. Currently, various molecular docking programs are extensively applied; therefore, realizing accuracy and performance of the various docking programs could have a significant value. In this comparative study, the performance and accuracy of three widely used non-commercial docking software (AutoDock Vina, 1-Click Docking, and UCSF DOCK) was evaluated through investigations of the predicted binding affinity and binding conformation of the same set of small molecules (HIV-1 protease inhibitors) and a protein target HIV-1 protease enzyme. The tested sets are composed of eight receptor-ligand complexes with high resolution crystal structures downloaded from Protein Data Bank website. Molecular dockings were applied between approved HIV-1 protease inhibitors and the HIV-1 protease using AutoDock Vina, 1-Click Docking, and DOCK6. Then, docking poses of the top-ranked solution was realized using UCSF Chimera. Furthermore, Pearson correlation coefficient (r) and coefficient of determination (r2) between the experimental results and the top scored docking results of each program were calculated using Graphpad prism V9.2. After comparing saquinavir top scored binding poses of each docking program with the crystal structure, various conformational changes were observed. Moreover, according to the relative comparison between the top ranked calculated ?Gbinding values against the experimental results, r2 value of AutoDock Vina, 1-Click Docking, and DOCK6 were 0.65, 0.41, and 0.005, respectively. The outcome of this study shows that the top scored binding free energy could not produce the best pose prediction. In addition, AutoDock Vina results have the highest correlation with the experimental results.

Antiretroviral protease inhibitors induce features of cellular senescence that are reversible upon drug removal.

Antiretroviral drugs have dramatically improved the prognosis of HIV-infected patients, with strikingly reduced morbidity and mortality. However, long-term use can be associated with signs of premature aging. Highly active antiretroviral therapy generally comprises two nucleoside reverse transcriptase inhibitors (NRTIs), with one of three additional antiretroviral drug classes, including protease inhibitors (PIs). One commonality between mitochondrial dysfunction (induced by NRTIs) and defects in lamin A (induced by PIs) is they can cause or accelerate cellular senescence, a state of essentially irreversible growth arrest, and the secretion of many bioactive molecules collectively known as the senescence-associated secretory phenotype (SASP). We hypothesized that senescent cells increase following treatment with certain HIV therapies. We compared the effects of two distinct HIV PIs: ritonavir-boosted atazanavir (ATV/r) and ritonavir-boosted darunavir (DRN/r), used in combination treatments for HIV infection. Upon ATV/r, but not DRN/r, treatment, cells arrested growth, displayed multiple features of senescence, and expressed significantly upregulated levels of many SASP factors. Furthermore, mice receiving sustained ATV/r treatment showed an increase in senescent cells and age-related decline in physiological function. However, removing treatment reversed the features of senescence observed in vivo and cell culture. Given how these features disappeared with drug removal, certain features of senescence may not be prognostic as defined by an irreversible growth arrest. Importantly, for patients that are treated or have been treated with ATV/r, our data suggest that switching to another PI that does not promote premature aging conditions (DRN/r) may improve the associated age-related complications.

In Silico Prediction of Biomarkers from Amaranthus tricolor (L) Targeted against HIV-1 Protease

Acquired immunodeficiency syndrome is caused by a retrovirus human immunodeficiency virus (HIV). Resistance to antiviral drugs is alarming in antiretroviral therapy and medical management of HIV-infected patients. Thus, identifying novel antiviral drugs is critical and medicinal plants are an excellent source for such discoveries. The current study aimed to isolate and characterize the chemical constituents from leaves of Amaranthus tricolor (L) and to discover novel HIV-1 protease inhibitors. Amaranthus tricolor methanolic extract (ATME) was fractionated into chloroform and aqueous phases. The chloroform fraction was separated by column chromatography using mobile phase n-hexane: ethyl acetate (6:4 v/v). Among various fractions, SOWIS-III was purified and studied for structural interpretation. The compounds were docked with HIV-1 protease as a drug target. The structural interpretation of the SOWIS-III fraction was identified as flavanol glycoside 24-methylene cycloartanol and SOWIS-P as a gallic acid derivative methyl 3,4,5-trihydroxybenzoate. The docking studies of 24-Methylenecycloartanol and HIV-1 protease showed 10 amino acid interactions with the estimated free energy of binding of -10.14 kcal/mol and the antiviral activity depicted as 36.88 nM. Methyl 3,4,5-trihydroxybenzoate and HIV-1 protease show five amino acid interactions with the estimated free energy of binding of -5.03 kcal/mol with 205.24 μM estimated antiviral activity. Hence, 24-methylene cycloartanol and methyl 3,4,5-trihydroxybenzoate can serve as drug candidates for HIV.

Structure based design and evaluation of benzoheterocycle derivatives as potential dual HIV-1 protease and reverse transcriptase inhibitors

The development of dual inhibitors of HIV-1 protease and reverse transcriptase is an attractive strategy for multi-target therapeutic of AIDS, which may be privileged in delaying the occurrence of drug resistance. We herein designed a novel kind of dual inhibitors with benzofuran or indole cores. Biological results showed that a number of inhibitors displayed significant activity against both HIV-1 protease and reverse transcriptase. Among which, inhibitor 10f exhibited a good correlation with an approximate ratio of 1: 2 between the two enzymes. Furthermore, the dual inhibitors illustrated similar potency against both the wild-type virus and drug-resistant mutant. In addition, the molecular dynamic simulation studies verified the dual actions of such inhibitors.

Current Insights and Molecular Docking Studies of the Drugs under Clinical Trial as RdRp Inhibitors in COVID-19 Treatment.

Docking studies were performed using the Maestro 12.9 module of Schrodinger software over 70 molecules with RdRp as the target and remdesivir as the standard drug and further confirmed by simulation studies. The docking studies showed that many HIV protease inhibitors demonstrated remarkable binding interactions with the target RdRp. Protease inhibitors such as lopinavir and ritonavir are effective. Along with these, AT-527, ledipasvir, bicalutamide, and cobicistat showed improved docking scores. RMSD and RMSF were further analyzed for potent ledipasvir and ritonavir by simulation studies and were identified as potential candidates for corona disease. The drug repurposing approach provides a new avenue in COVID-19 treatment.

Expanding the therapeutic options for Candida infections using novel inhibitors of secreted aspartyl proteases.

For widening the therapeutic options for Candida management, the druggability of Candida proteome was systematically investigated using an innovative pipeline of high-throughput data mining algorithms, followed by in vitro validation of the observations. Through this exercise, HIV-1 protease was found to share structural similarity with secreted aspartyl protease-3 (SAP3), a virulence protein of Candida. Using the molecular fingerprint of HIV-1 protease inhibitor GRL-09510, we performed virtual screening of peptidomimetic library followed by high-precision docking and MD simulations for discovery of SAP inhibitors. Wet-lab validation of the four shortlisted peptidomimetics revealed that two molecules, when used in combination with fluconazole, could significantly reduce the dosage of fluconazole required for 50% inhibition of Candida albicans. The SAP inhibitory activity of these peptidomimetics was confirmed through SAP assays and found to be on par with pepstatin A, a known peptidomimetic inhibitor of aspartyl proteases.

Design and Evaluation of Novel HIV-1 Protease Inhibitors Containing Phenols or Polyphenols as P2 Ligands with High Activity against DRV-Resistant HIV-1 Variants.

With the increasing prevalence of drug-resistant variants, novel potent HIV-1 protease inhibitors with broad-spectrum antiviral activity against multidrug-resistant causative viruses are urgently needed. Herein, we designed and synthesized a new series of HIV-1 protease inhibitors with phenols or polyphenols as the P2 ligands and a variety of sulfonamide analogs as the P2' ligands. A number of these new inhibitors showed superb enzymatic inhibitory activity and antiviral activity. In particular, inhibitors 15d and 15f exhibited potent enzymatic inhibitory activity in the low picomolar range, and the latter showed excellent activity against the Darunavir-resistant HIV-1 variant. Furthermore, the molecular modeling studies provided insight into the ligand-binding site interactions between inhibitors and the enzyme cavity, and they sparked inspiration for the further optimization of potent inhibitors.

HIV protease inhibitor attenuated astrocyte autophagy involvement in inflammation via p38 MAPK pathway

HIV-associated neurocognitive disorder (HAND) is prevalent in people living with HIV, despite the use of antiretroviral therapy (ART). Although several risk factors have been proposed to be related to HAND, substantial effort has been made to explore the neurotoxic effects of ART on HAND. HIV protease inhibitor (PI), an essential component of ART, has neurotoxicity in vivo and in vitro, which can contribute to the development of HAND. However, the pathogenesis of PI-associated neurotoxicity remains unclear. Here, we explored whether PI treatment is a potential pathogenic factor for HAND and elucidated its potential mechanisms. In our study, U87 cells were exposed to PIs, including lopinavir (LPV), ritonavir (RTV), darunavir, indinavir, and saquinavir at different concentrations, we found that LPV, LPV/RTV, and saquinavir attenuated autophagy in U87 cells, the results of Western blot showed that the expression of p62 dramatically was elevated and the level of LC3II/LC3I was decreased. Moreover, comparative transcriptomics revealed the involvement of the inflammatory response in the physiological activities of U87 cells exposed to LPV, with differential genes significantly enriched in the p38 MAPK signaling pathway. In the following study, we verified the results from RNA-sequence using the liquid chip technique, qRT-PCR, Elisa, and western blots, which suggested that LPV induced inflammatory response and the p38 MAPK pathway was involved in this process. Collectively, we demonstrated that PIs attenuated the involvement of astrocyte autophagy in inflammation via the p38 MAPK pathway, providing new insights into the mechanism of HAND.

Prediction of HIV-1 protease cleavage site from octapeptide sequence information using selected classifiers and hybrid descriptors

BackgroundIn most parts of the world, especially in underdeveloped countries, acquired immunodeficiency syndrome (AIDS) still remains a major cause of death, disability, and unfavorable economic outcomes. This has necessitated intensive research to develop effective therapeutic agents for the treatment of human immunodeficiency virus (HIV) infection, which is responsible for AIDS. Peptide cleavage by HIV-1 protease is an essential step in the replication of HIV-1. Thus, correct and timely prediction of the cleavage site of HIV-1 protease can significantly speed up and optimize the drug discovery process of novel HIV-1 protease inhibitors. In this work, we built and compared the performance of selected machine learning models for the prediction of HIV-1 protease cleavage site utilizing a hybrid of octapeptide sequence information comprising bond composition, amino acid binary profile (AABP), and physicochemical properties as numerical descriptors serving as input variables for some selected machine learning algorithms. Our work differs from antecedent studies exploring the same subject in the combination of octapeptide descriptors and method used. Instead of using various subsets of the dataset for training and testing the models, we combined the dataset, applied a 3-way data split, and then used a "stratified" 10-fold cross-validation technique alongside the testing set to evaluate the models.ResultsAmong the 8 models evaluated in the “stratified” 10-fold CV experiment, logistic regression, multi-layer perceptron classifier, linear discriminant analysis, gradient boosting classifier, Naive Bayes classifier, and decision tree classifier with AUC, F-score, and B. Acc. scores in the ranges of 0.91–0.96, 0.81–0.88, and 80.1–86.4%, respectively, have the closest predictive performance to the state-of-the-art model (AUC 0.96, F-score 0.80 and B. Acc. ~ 80.0%). Whereas, the perceptron classifier and the K-nearest neighbors had statistically lower performance (AUC 0.77–0.82, F-score 0.53–0.69, and B. Acc. 60.0–68.5%) at p < 0.05. On the other hand, logistic regression, and multi-layer perceptron classifier (AUC of 0.97, F-score > 0.89, and B. Acc. > 90.0%) had the best performance on further evaluation on the testing set, though linear discriminant analysis, gradient boosting classifier, and Naive Bayes classifier equally performed well (AUC > 0.94, F-score > 0.87, and B. Acc. > 86.0%).ConclusionsLogistic regression and multi-layer perceptron classifiers have comparable predictive performances to the state-of-the-art model when octapeptide sequence descriptors consisting of AABP, bond composition and standard physicochemical properties are used as input variables. In our future work, we hope to develop a standalone software for HIV-1 protease cleavage site prediction utilizing the linear regression algorithm and the aforementioned octapeptide sequence descriptors.

Repurposing HIV Protease Inhibitors Atazanavir and Darunavir as Antifungal Treatments against Candida albicans Infections: An In Vitro and In Vivo Study

Candida albicans is the chief etiological agent of candidiasis, a mycosis prevalent in individuals with acquired immunodeficiency syndrome (AIDS). In recent years, the introduction of human immunodeficiency virus (HIV) protease inhibitors (HIV-PI) has reduced the prevalence of candidiasis in these patients. Seeking new therapeutic strategies based on the perspective of drug repositioning, we evaluated the effects of two second-generation HIV-PIs, atazanavir (ATV) and darunavir (DRV), on virulence factors of C. albicans and experimental candidiasis. For this, clinical strains of C. albicans were subjected to in vitro and in vivo treatments with ATV or DRV. As a result, ATV and DRV exhibited antifungal activity against fungal cells at 512 μg/mL, reduced the viability and biomass of biofilms, and inhibited filamentation of C. albicans. In addition, these HIV-PIs downregulated the expression of SAP2 and BRC1 genes of C. albicans. In an in vivo study, prophylactic use of ATV and DRV prolonged the survival rate of Galleria mellonella larvae infected with C. albicans. Therefore, ATV and DRV showed activity against C. albicans by reducing cell growth, biofilm formation, filamentation, and expression of virulence genes. Furthermore, ATV and DRV decreased experimental candidiasis, suggesting the repurposing of HIV-PIs as antifungal treatments for C. albicans infections.

Potent and biostable inhibitors of the main protease of SARS-CoV-2

Potent and biostable inhibitors of the main protease (Mpro) of SARS-CoV-2 were designed and synthesized based on an active hit compound 5h (2). Our strategy was based not only on the introduction of fluorine atoms into the inhibitor molecule for an increase of binding affinity for the pocket of Mpro and cell membrane permeability but also on the replacement of the digestible amide bond by a surrogate structure to increase the biostability of the compounds. Compound 3 is highly potent and blocks SARS-CoV-2 infection invitro without a viral breakthrough. The derivatives, which contain a thioamide surrogate in the P2-P1 amide bond of these compounds (2 and 3), showed remarkably preferable pharmacokinetics in mice compared with the corresponding parent compounds. These data show that compounds 3 and its biostable derivative 4 are potential drugs for treating COVID-19 and that replacement of the digestible amide bond by its thioamide surrogate structure is an effective method.

A Phase II Study of Nelfinavir plus Concurrent Chemoradiation for Advanced, HPV-Negative Squamous Cell Carcinoma of the Head and Neck

<h3>Purpose/Objective(s)</h3> Locoregional control of advanced HPV-negative head and neck squamous cell carcinomas remains a challenge, with tumor hypoxia adversely affecting radiation efficacy and outcomes in patients treated with chemoradiation. Nelfinavir is a HIV protease inhibitor that has also shown promise as an anti-hypoxia agent, via decreasing tumor oxygen consumption. We conducted a single-arm, phase II study of Nelfinavir plus chemoradiation to assess whether Nelfinavir could improve locoregional control as a hypoxic radiosensitizer. <h3>Materials/Methods</h3> Patients with biopsy-proven AJCC v7 stage III or IV (excluding M1) HPV-negative squamous cell carcinomas of the oral cavity, oropharynx, larynx, or hypopharynx were eligible. Patients were treated with definitive chemo(bio)radiotherapy and received oral Nelfinavir (1250 mg twice a day), starting with a ‘lead-in' period of Nelfinavir for 10-14 days prior to initiation of chemoradiation, and continued during chemoradiation. PET/CT imaging to assess glucose metabolic activity (¹⁸F-FDG-PET) and hypoxia (¹⁸F-MISO or ¹⁸F-EF5) was obtained at baseline (prior to starting Nelfinavir), and again after Nelfinavir lead-in (prior to initiation of chemoradiation). The primary outcome was locoregional control, with secondary outcomes of distant metastasis-free survival, overall survival, and the effect of Nelfinavir on hypoxia and glucose metabolism as assessed via PET/CT. <h3>Results</h3> A total of 17 patients were enrolled with a median 2.72 year follow up. Patient characteristics are shown in Table 1. At most recent follow up, locoregional control was 76.5% (13/17 patients), with distant metastasis free survival of 70.6% (12/17 patients), and overall survival of 47.1% (8/17 patients). Three (17.6%) patients discontinued Nelfinavir due to toxicity, with elevated liver function tests in 2 (11.8%) and diarrhea in 1 (5.9%). <h3>Conclusion</h3> The addition of Nelfinavir to definitive chemoradiation shows promising locoregional control in HPV-negative locally advanced squamous cell carcinoma of the head and neck. These results compare favorably to patients with identified hypoxic head and neck cancers treated with chemoradiation alone (38% locoregional control, TROG 98.02 trial, Rischin et al. JCO 2006). These results warrant further investigation in cancers where locoregional control with standard approaches remains a limiting factor.

Progress in Synthesis of Glycidol

The molecular structure of glycidol contains two highly active chemical functional groups, epoxy group and hydroxyl group, so it is very active and is a very useful chemical substance. It can be used as plastics, fiber modifiers, epoxy resin diluents, halogenated hydrocarbon stabilizers, food preservatives, fungicides, etc. In the pharmaceutical field, it can be used to synthesize a series of blockers for cardiovascular diseases, HIV protease inhibitor for AIDS, antiviral drug, many lactones and glycerophospholipid, it can also be used as an important intermediate of some photoelectric materials and functional polymer materials. The partial reactivity of glycidyl depends on its epoxy ring acting as an alkylating agent. In addition, it is used in the production of flavorings and sweeteners. Glycidyl can also be used as a stabilizer, used in the production of petroleum, vinyl polymers, demulsifiers, dyeing layered agents and gelata applied in surface coatings, chemical synthesis, fungicides, solid fuels. It's also an important monomer and semi-finished product for synthetic surfactant. And its derivatives are also a kind of chemical raw materials, which are used in many fields such as resins, plastics, medicines, pesticides and auxiliaries. Therefore, more and more attention are paid to the synthesis and application of glycidol. However, the application of glycerol in our country is limited, and the industrial production is also lagging behind. In this paper, the process of glycidol synthesis form propylene alcohol and glycerol as basic raw material was reviewed, and the preparation of glycidol was systematically summarized, so as to provide reference for the subsequent research of glycidol.

Organosilane as potent HIV-1 protease inhibitors and its hybrid silica nanoparticles as a “turn-off” fluorescent sensor for silver ion recognition

This article presents the azide-alkyne cycloaddition interaction to make an organosilane-based sensor that was mounted on the outer layer of hybrid silica nanoparticles. Both organosilanes were very much portrayed utilizing different spectroscopic strategies. In general, the discoveries show that this technique for making novel utilitarian materials might be used to successfully identify Ag+ particles. The expansion of silicon to the field of nanoscience offers a huge advantage, as silica-based nanomaterials can give more prominent enhancements. The subsequent hybrid nanoparticles (H-NPs) were distinguished utilizing different physicochemical and insightful strategies, and these nanocomposites likewise showed a critical liking for Ag+ particles when contrasted with their forerunner, with a limit of detection (LOD) worth of 3.19 × 10−7 Mwhereas organosilane shows a LOD value of 2.86 × 10−6 M. To acquire an understanding of the complexation system of 5a with Ag+ particles, a computational examination was done utilizing the DFT method. Molecular docking research with the Human immunodeficiency virus 1 (HIV-1) protease was undertaken to investigate the biological outcomes of triazole-based organosilane, and the chosen ligand was shown to have a satisfactory docking score with a binding energy of −7.67 kcal mol−1.

Anti-HIV Ermiasolides from Croton megalocarpus.

In recent years, elucidation of novel anti-HIV bioactive compounds from natural products is gaining importance rapidly, not only from the research and publications, but also from controlled clinical studies. Here we report three new anti-HIV eudesmane-type sesquiterpenes, 5β-Hydroxy-8α-methoxy eudesm-7(11)-en-12,8-olide (1), 5β,8α-Dihydroxy eudesm-7(11)-en-12,8-olide (2) and 5β-Hydroxy-8H-β-eudesm-7(11)-en-12,8-olide (3). These are trivially named ermiasolide A-C and were isolated from the bark of Croton megalocarpus. 5β-Hydroxy-8α-methoxy eudesm-7(11)-en-12,8-olide (1), showed the highest anti-HIV activity by inhibiting 93% of the viral replication with an IC50 = 0.002 µg/mL. On the other hand, 5β-Hydroxy-8H-β-eudesm-7(11)-en-12,8-olide (3) and 5β,8α-dihydroxy eudesm-7(11)-en-12,8-olide (2), inhibited viral replication by 77.5% at IC50 = 0.04 µg/mL and 69.5% at IC50 = 0.002 µg/mL, respectively. Molecular docking studies showed that the proposed mechanism of action leading to these results is through the inhibition of HIV-protease.

A Non-Peptidic Protease Inhibitor for HIV Treatment

Key words HIV protease inhibitor - non-peptidic inhibitor - process chemistry - Curtius rearrangement - Grignard reagents