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Gerrit Kann,1,* Junaid Owasil,1,* Karina Kuczka,2 Annette Haberl,1 Timo Wolf,1 Pavel Khaykin,1 Sebastian Harder,2 Christoph Stephan,1 Nils von Hentig1 1HIVCENTER, Medical HIV Treatment and Research Unit, Johann Wolfgang Goethe University Frankfurt, Frankfurt am Main, Germany; 2Pharmazentrum Frankfurt, Institute of Clinical Pharmacology, Johann Wolfgang Goethe University Frankfurt, Frankfurt am Main, Germany*These authors contributed equally to this workCorrespondence: Nils von HentigHIVCENTER, Medical HIV Treatment and Research Unit, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, Frankfurt am Main, 60590, GermanyTel +49-69-63017680Fax +49-69-630183442Email Hentig@em.uni-frankfurt.deBackground: In the past, protease inhibitors (PIs) and the reverse transcriptase inhibitor abacavir were identified increasing the risk for thromboembolic complications and cardiovascular events (CVE) of HIV infected patients taking a combination antiretroviral therapy (cART). Results of the previous HIV-PLA I-study lead to the assumption that platelet activation could play a substantial role in increasing CVE risks.Methods: The open label, monocentric HIV-PLA II-study investigated HIV-1-infected, therapy-naïve adults (n=45) starting with cART, consisting either of boosted PI (atazanavir, n= 6, darunavir, n=11), NNRTI (efavirenz, n=14) or integrase inhibitor (raltegravir, n=14), each plus tenofovir/emtricitabine co-medication. Main exclusion criteria were tobacco smoking, the intake of NSAIDs or abacavir or past CVE. Platelet adhesive molecule p-selectin (CD62P) and FITC anti-human Integrin α-IIb/Integrin β-3 (CD41/CD61) antibody (PAC-1) binding, monocyte CD11b/monocyte-associated CD41 expression and the endogenous thrombin potential (ETP) were assessed ex vivo-in vitro at baseline, weeks 4, 12 and 24. Therapy regimens were blinded to the investigators for laboratory and statistical analyses.Results: CD11b and ETP showed no significant changes or differences between all study groups. In contrast, the mean + SD mean fluorescence units (MFI) of CD62P and PAC-1 increased significantly in patients taking PI, indicating an enhanced potential for thrombocyte activation and aggregation.Conclusion: CD62P expression, detecting the ɑ-platelet degranulation of pro-inflammatory and pro-thrombotic factors and adhesive proteins, and PAC-1 expression, representing a marker for conformation changes of the GIIb/IIIa receptor, increased significantly in patients taking HIV protease inhibitors. The findings of this study revealed a yet unknown pathway of platelet activation, possibly contributing to the increased risk for CVE under HIV protease inhibitor containing cART.Clinical Trial Registration No.: DRKS00000288.Keywords: HIV protease inhibitors, platelets, leucocytes, PAC-1, GIIb/IIIa-receptor

Further, as combination therapy is often required for the treatment of aggressive B cell malignancies, the identification of therapies that synergistically combine with MALT1 inhibitors could afford additional and promising treatment options. B Introduction: b Specific B cell malignancies, including CLL and the aggressive non-GCB subtype of DLBCL, are driven by constitutive activation of the B cell receptor (BCR) pathway and the transcription factor NF- B. Pharmacological inhibition of MALT1 protease, a key mediator of the BCR/NF- B signal transduction pathway, may therefore provide an attractive treatment option for patients with these cancers. [Extracted from the article]

BackgroundNucleos(t)ide reverse transcriptase inhibitor (NRTI)-sparing regimens may potentially minimize antiretroviral (ART) toxicities, but demonstrate mixed efficacy and toxicity results. The impact of an integrase strand transfer inhibitor (INSTI) and protease inhibitor (PI) regimen on HIV viral dynamics and T cell kinetics remains underdescribed.ObjectiveTo compare the effect of raltegravir + ritonavir boosted lopinavir (RAL + LPV/r) to efavirenz/tenofovir disoproxil fumarate/emtricitabine (EFV/TDF/FTC) on HIV kinetics and T cell dynamics.MethodsFifty participants naïve to ART underwent HIV viral kinetic sampling evaluated using biexponential mixed effects modeling. A subset of 28 subjects (with complete viral suppression) underwent flow cytometry and evaluation of soluble markers of inflammation at weeks 0, 4, and 48 of ART.ResultsRAL + LPV/r compared to EFV/TDF/FTC resulted in a prolonged first phase viral decay rate (18 vs. 13 days p

PurposeClinically relevant pharmacokinetic interactions exist between gastric acid-reducing agents and certain weakly basic drugs that rely on acidic environments for optimal oral absorption. In this study, we examine whether the administration of betaine hydrochloride under fed conditions can enhance the absorption of atazanavir, an HIV-1 protease inhibitor, during pharmacologically-induced hypochlorhydria.MethodsIn this randomized, single-dose, 3 period, crossover study healthy volunteers received ritonavir-boosted atazanavir (atazanavir/ritonavir 300/100 mg) alone, following pretreatment with the proton pump inhibitor rabeprazole (20 mg twice daily), and with 1500 mg of betaine HCl after rabeprazole pretreatment. Atazanavir was administered with a light meal and gastric pH was monitored using the Heidelberg Capsule.ResultsPretreatment with rabeprazole resulted in significant reductions in atazanavir Cmax (p

Kinetic properties may serve as critical differentiators and predictors of drug efficacy and safety, in addition to the traditionally focused binding affinity. However the quantitative structure-kinetics relationship (QSKR) for modeling and ligand design is still poorly understood. This review provides an introduction to the kinetics of drug binding from a fundamental chemistry perspective. We focus on recent developments of computational tools and their applications to non-covalent binding kinetics.

The HIV protease inhibitor lopinavir inhibits Plasmodium falciparum aspartic proteases (plasmepsins) and parasite development, and children receiving lopinavir-ritonavir experienced fewer episodes of malaria than those receiving other antiretroviral regimens. Resistance to lopinavir was selected in vitro over ∼9 months, with ∼4-fold decreased sensitivity. Whole-genome sequencing of resistant parasites showed a mutation and increased copy number in pfmdr1 and a mutation in a protein of unknown function, but no polymorphisms in plasmepsin genes.

Summary: Background: Alveolar echinococcosis (AE), which is caused by larval Echinococcus multilocularis, is one of the world's most dangerous neglected diseases. Currently, no fully effective treatments are available to cure this disease. Methods: In vitro protoscolicidal assay along with in vivo murine models was applied in repurposing drugs against AE. Genome-wide identification and homology-based modeling were used for predicting drug targets. RNAi, enzyme assay, and RNA-Seq analyses were utilized for investigating the roles in parasite survival and validations for the drug target. Findings: We identified nelfinavir as the most effective HIV protease inhibitor against larval E. multilocularis. Once-daily oral administration of nelfinavir for 28 days resulted in a remarkable reduction in parasite infection in either immune-competent or immunocompromised mice. E. multilocularis DNA damage-inducible 1 protein (EmuDdi1) is predicted as a target candidate for nelfinavir. We proved that EmuDdi1 is essential for parasite survival and protein excretion and acts as a functionally active protease for this helminth. We found nelfinavir is able to inhibit the proteolytic activity of recombinant EmuDdi1 and block the EmuDdi1-related pathways for protein export. With other evidence of drug efficacy comparison, our results suggest that inhibition of EmuDdi1 is a mechanism by which this HIV proteinase inhibitor mediates its antiparasitic action on echinococcosis. Interpretation: This study demonstrates that nelfinavir is a promising candidate for treating echinococcosis. This drug repurposing study proves that the widely prescribed drug for AIDS treatment is potent in combating E. multilocularis infection and thus provides valuable insights into the development of single-drug therapy for highly prevalent co-infection between HIV and helminth diseases. Funding: This work was supported by the National Natural Science Foundation of China (31802179), the Natural Science Foundation of Gansu Province, China (No. 21JR7RA027), and the State Key Laboratory of Veterinary Etiological Biology (No. SKLVEB2021YQRC01).

The human DNA repair enzyme AlkB homologue-2 (ALKBH2) repairs methyl adducts from genomic DNA and is overexpressed in several cancers. However, there are no known inhibitors available for this crucial DNA repair enzyme. The aim of this study was to examine whether the first-generation HIV protease inhibitors having strong anti-cancer activity can be repurposed as inhibitors of ALKBH2. We selected four such inhibitors and performed in vitro binding analysis against ALKBH2 based on alterations of its intrinsic tryptophan fluorescence and differential scanning fluorimetry. The effect of these HIV protease inhibitors on the DNA repair activity of ALKBH2 was also evaluated. Interestingly, we observed that one of the inhibitors, ritonavir, could inhibit ALKBH2-mediated DNA repair significantly via competitive inhibition and sensitized cancer cells to alkylating agent methylmethane sulfonate (MMS). This work may provide new insights into the possibilities of utilizing HIV protease inhibitor ritonavir as a DNA repair antagonist. • Four HIV drugs with anti-cancer properties were evaluated as ALKBH2 antagonist. • Intrinsic Trp fluorescence quenching showed that ritonavir binds to ALKBH2. • Thermal unfolding showed ritonavir binding requires ALKBH2 R110 residue. • Enzyme kinetics results suggested that ritonavir competitively inhibits ALKBH2. • Ritonavir exposure reduced cancer cell survival following MMS treatment. [ABSTRACT FROM AUTHOR]

The availability of drugs capable of blocking the replication of microorganisms has been one of the greatest triumphs in the history of medicine, but the emergence of an ever-increasing number of resistant strains poses a serious problem for the treatment of infectious diseases. The search for new potential ligands for proteins involved in the life cycle of pathogens is, therefore, an extremely important research field today. In this work, we have considered the HIV-1 protease, one of the main targets for AIDS therapy. Several drugs are used today in clinical practice whose mechanism of action is based on the inhibition of this enzyme, but after years of use, even these molecules are beginning to be interested by resistance phenomena. We used a simple artificial intelligence system for the initial screening of a data set of potential ligands. These results were validated by docking and molecular dynamics, leading to the identification of a potential new ligand of the enzyme which does not belong to any known class of HIV-1 protease inhibitors. The computational protocol used in this work is simple and does not require large computational power. Furthermore, the availability of a large number of structural information on viral proteins and the presence of numerous experimental data on their ligands, with which it is possible to compare the results obtained with computational methods, make this research field the ideal terrain for the application of these new computational techniques.

The resistance of HIV-1 protease (PR) mutations seriously affects the efficiency of current drugs in the clinical treatment of AIDS. Therefore, it is important to understand the resistance mechanism of mutated residues for the development of PR inhibitors. In this work, the mechanism of G48M mutant PR to inhibitors Saquinavir and Atazanavir was studied by using molecular dynamics simulation combined with free energy prediction. The analysis results showed that, compared with the WT PR, the distance of the flap tip from the protease catalytic binding site and the dihedral angles in the flap regions in the mutant type complexes was changed. These changes resulted in a significant reduction in the occupancy of most of the hydrogen bonds in the mutant complex and the interaction energy of key residues with the inhibitor, which is the main reason for the resistance of the mutation to these inhibitors. This study can provide important guidance for the design of effective inhibitors against HIV-1 PR. [ABSTRACT FROM AUTHOR]

The action of proteases can be controlled by several mechanisms, including regulation through gene expression; post-translational modifications, such as glycosylation; zymogen activation; targeting specific compartments, such as lysosomes and mitochondria; and blocking proteolysis using endogenous inhibitors. Protease inhibitors are important molecules to be explored for the control of proteolytic processes in organisms because of their ability to act on several proteases. In this context, plants synthesize numerous proteins that contribute to protection against attacks by microorganisms (fungi and bacteria) and/or invertebrates (insects and nematodes) through the inhibition of proteases in these organisms. These proteins are widely distributed in the plant kingdom, and are present in higher concentrations in legume seeds (compared to other organs and other botanical families), motivating studies on their inhibitory effects in various organisms, including humans. In most cases, the biological roles of these proteins have been assigned based mostly on their in vitro action, as is the case with enzyme inhibitors. This review highlights the structural evolution, function, and wide variety of effects of plant Kunitz protease inhibitors, and their potential for pharmaceutical application based on their interactions with different proteases. [ABSTRACT FROM AUTHOR]

Although several proteasome subunits have been shown to bind ubiquitin (Ub) chains, many ubiquitylated substrates also associate with 26S proteasomes via "shuttling factors." Unlike the well-studied yeast shuttling factors Rad23 and Dsk2, vertebrate homologs Ddi2 and Ddi1 lack a Ub-associated domain; therefore, it is unclear how they bind Ub. Here, we show that deletion of Ddi2 leads to the accumulation of Ub conjugates with K11/K48 branched chains. We found using affinity copurifications that Ddi2 binds Ub conjugates through its Ub-like domain, which is also required for Ddi2 binding to proteasomes. Furthermore, in cell extracts, adding Ub conjugates increased the amount of Ddi2 associated with proteasomes, and adding Ddi2 increased the binding of Ub conjugates to purified proteasomes. In addition, Ddi2 also contains a retroviral protease domain with undefined cellular roles. We show that blocking the endoprotease activity of Ddi2 either genetically or with the HIV protease inhibitor nelfinavir increased its binding to Ub conjugates but decreased its binding to proteasomes and reduced subsequent protein degradation by proteasomes leading to further accumulation of Ub conjugates. Finally, nelfinavir treatment required Ddi2 to induce the unfolded protein response. Thus, Ddi2 appears to function as a shuttling factor in endoplasmic reticulum-associated protein degradation and delivers K11/K48-ubiquitylated proteins to the proteasome. We conclude that the protease activity of Ddi2 influences this shuttling factor activity, promotes protein turnover, and helps prevent endoplasmic reticulum stress, which may explain nelfinavir's ability to enhance cell killing by proteasome inhibitors. [ABSTRACT FROM AUTHOR]

Background Coronavirus disease 2019 (COVID-19) has resulted in a huge burden on healthcare systems, especially on programs for chronic illnesses such as HIV. We aimed to assess the challenges confronting adult people living with HIV (PLHIV) in three countries in North Africa during the COVID-19 crisis and their awareness of COVID-19 non-pharmaceutical preventive measures. Methods This online survey included PLHIV aged ≥18 y from three countries in North Africa recruited by a snowball sampling technique, who were asked to complete a modified questionnaire originally developed by the University of Antwerp in Belgium, which was then disseminated through social media tools to assess the study outcomes. Results Out of 369 respondents, 260 (70.5%) were males and 237 (64.2%) were aged 18–39 y. Adherence to COVID-19 preventive measures, wearing facemasks (308 [83.2%]), applying hand-sanitizers (299 [80.8%]) and following cough etiquette (261 [70.5%]), were predominantly reported. Only 48 (13%) were vaccinated against influenza. One hundred and forty-five participants (42%) experienced flu-like symptoms, 29 (20%) were tested for COVID-19, with only one confirmed case identified. Among 344 (93.2%) on antiretroviral therapy (73.8% efavirenz- vs 6.4% dolutegravir-based regimens), 219 (63.7%) attended their scheduled visits, 144 (41.9%) had limited access to care due to lockdown and 29 (8.4%) became less adherent to their antiretroviral therapy. Covariates associated with challenges during access to care were age ≥60 y (OR=6.5; 95% CI 1.8 to 23.2) and receiving second-line HIV treatment such as protease inhibitors (OR=2.7; 95% CI 1.3 to 5.8). Conclusion The pandemic adversely affected PLHIV. New innovative strategies should be implemented to ensure the continuity of HIV services. [ABSTRACT FROM AUTHOR]

This paper describes the structure-based design and synthesis of two novel square-planar trans-N2O2 Cu(II) complexes [Cu(L1)2] (1) and [Cu(L2)2] (2) of 2-((Z)-(4-methoxyphenylimino)methyl)-4,6-dichlorophenol (L1H) and 2-((Z)-(2,4-dibromophenylimino)methyl)-4-bromophenol (L2H) as potential inhibitors against the main protease of the SARS-CoV-2 and HIV viruses. Copper complexes (1) and (2) crystallize in a monoclinic crystal system with P21/n and P21/c space groups, respectively [a = 12.4630(12) Å, b = 9.2765(10) Å, c = 12.6425(13) Å, α = 90°, β = 111.863°, γ = 90° and Z = 2 for [Cu(L1)2] (1); a = 10.1185(13) Å, b = 10.9809(12) Å, c = 12.5803(13) Å, α = 90°, β = 103.795°, γ = 90°, and Z = 2 for [Cu(L2)2] (2)]. Single crystal X-ray diffraction studies revealed that both complexes exhibit square-planar geometry (τ = 0). Quantum computational calculations were used for the structure–property relationship. Detailed structural and non-covalent supramolecular interactions in the complexes were investigated by single crystal structure analysis and computational approaches. Hirshfeld surface and 2D fingerprint plots were explored in the crystal structure of the complexes. The strength of the interaction and 3D topology of the crystal packing are visualized through an energy framework. Further, inspired by recent developments to find a structure-based drug design for inhibitors of the SARS-CoV-2 main protease, molecular docking of the copper complexes with the SARS-CoV-2 main protease for COVID-19 was performed. The X-ray crystallographic structures of the main protease of the SARS-CoV-2 virus (PDB ID: 6XBG) and HIV virus (PDB ID: 1JLE and 1UUD) were retrieved from the protein data bank and used as receptor proteins. The molecular docking calculations of complexes (1) and (2) with SARS-CoV-2 virus revealed binding affinities of −9.8 kcal mol−1 and −9.4 kcal mol−1 with inhibition constants of 2.912 μM and 2.813 μM, respectively, at the inhibition binding site of the receptor protein. Besides this, molecular docking against HIV-1 reverse transcriptase (PDB ID: 1JLE) and HIV-1 TAR RNA (PDB ID: 1UUD) were also studied. The molecular docking results also showed that copper complexes with HIV-1 and HIV-1 RNA exhibited good binding affinities and inhibition constants at the binding site of the receptor protein. It was observed that the binding affinities of the copper complexes towards SARS-CoV-2 were comparatively higher than towards the HIV virus. Overall, an in silico molecular docking study suggests the potential role of copper complexes as antivirus drug candidates targeting the SARS-CoV-2 Mpro and HIV protease inhibitors. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Herein, we report an iridium‐catalyzed asymmetric hydrogenation of hydantoin and thiazolidinedione derived exocyclic alkenes using our developed BiphPHOX as a ligand. The transformation shows good functional group tolerance, and gives the hydrogenated products with excellent yields (up to 99%) and enantioselectivities (up to 98% ee). A gram‐scale reaction was also carried out, and provided the hydrogenated product in excellent yield with no erosion in enantioselectivity. Finally, the transformation of the hydrogenated product provided an efficient approach for the synthesis of the intermediate of a HIV protease inhibitor. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome 2 (SARS-CoV-2), has been one of the most devastating pandemics of recent times. The lack of potent novel antivirals had led to global health crises; however, emergence and approval of potent inhibitors of the viral main protease (Mpro), such as Pfizer's newly approved nirmatrelvir, offers hope not only in the therapeutic front but also in the context of prophylaxis against the infection. By their nature, RNA viruses including human immunodeficiency virus (HIV) have inherently high mutation rates, and lessons learnt from previous and currently ongoing pandemics have taught us that these viruses can easily escape selection pressure through mutation of vital target amino acid residues in monotherapeutic settings. In this paper, we review nirmatrelvir and its binding to SARS-CoV-2 Mpro and draw a comparison to inhibitors of HIV protease that were rendered obsolete by emergence of resistance mutations, emphasizing potential pitfalls in the design of inhibitors that may be of important relevance to the long-term use of novel inhibitors against SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Cervical cancer is a Human Papilloma virus-related disease, which is on the rise in a number of countries, globally. Two essential oncogenes, E6 and E7, drive cell transformation and cancer development. These two oncoproteins target two of the most important tumour suppressors, p53 and pRB, for degradation through the ubiquitin ligase pathway, thus, blocking apoptosis activation and deregulation of cell cycle. This pathway can be exploited for anticancer therapeutic interventions, and Human Immunodeficiency Virus Protease Inhibitors (HIV-PIs) have attracted a lot of attention for this anticancer drug development. HIV-PIs have proven effective in treating HPV-positive cervical cancers and shown to restore impaired or deregulated p53 in HPV-associated cervical cancers by inhibiting the 26S proteasome. This review will evaluate the role players, such as HPV oncoproteins involved cervical cancer development and how they are targeted in HIV protease inhibitors-induced p53 restoration in cervical cancer. This review also covers the therapeutic potential of HIV protease inhibitors and molecular mechanisms behind the HIV protease inhibitors-induced p53-dependent anticancer activities against cervical cancer.

Off-target binding of hydrophobic drugs can lead to unwanted side effects, either through specific or non-specific binding to unintended membrane protein targets. However, distinguishing the binding of drugs to membrane proteins from that of detergents, lipids and cofactors is challenging. Here, we use high-resolution mass spectrometry to study the effects of HIV protease inhibitors on the human zinc metalloprotease ZMPSTE24. This intramembrane protease plays a major role in converting prelamin A to mature lamin A. We monitored the proteolysis of farnesylated prelamin A peptide by ZMPSTE24 and unexpectedly found retention of the C-terminal peptide product with the enzyme. We also resolved binding of zinc, lipids and HIV protease inhibitors and showed that drug binding blocked prelamin A peptide cleavage and conferred stability to ZMPSTE24. Our results not only have relevance for the progeria-like side effects of certain HIV protease inhibitor drugs, but also highlight new approaches for documenting off-target drug binding.

BackgroundThe p6 region of the HIV-1 structural precursor polyprotein, Gag, contains two motifs, P7TAP11 and L35YPLXSL41, designated as late (L) domain-1 and -2, respectively. These motifs bind the ESCRT-I factor Tsg101 and the ESCRT adaptor Alix, respectively, and are critical for efficient budding of virus particles from the plasma membrane. L domain-2 is thought to be functionally redundant to PTAP. To identify possible other functions of L domain-2, we examined this motif in dominant viruses that emerged in a group of 14 women who had detectable levels of HIV-1 in both plasma and genital tract despite a history of current or previous antiretroviral therapy.ResultsRemarkably, variants possessing mutations or rare polymorphisms in the highly conserved L domain-2 were identified in seven of these women. A mutation in a conserved residue (S40A) that does not reduce Gag interaction with Alix and therefore did not reduce budding efficiency was further investigated. This mutation causes a simultaneous change in the Pol reading frame but exhibits little deficiency in Gag processing and virion maturation. Whether introduced into the HIV-1 NL4-3 strain genome or a model protease (PR) precursor, S40A reduced production of mature PR. This same mutation also led to high level detection of two extended forms of PR that were fairly stable compared to the WT in the presence of IDV at various concentrations; one of the extended forms was effective in trans processing even at micromolar IDV.ConclusionsOur results indicate that L domain-2, considered redundant in vitro, can undergo mutations in vivo that significantly alter PR function. These may contribute fitness benefits in both the absence and presence of PR inhibitor.

BackgroundRilpivirine pharmacokinetics is defined by its absorption, distribution, metabolism, and excretion. Pregnancy can affect these factors by changes in cardiac output, protein binding, volume of distribution, and cytochrome P450 (CYP) 3A4 activity. Rilpivirine is metabolized by CYP3A4. The impact of pregnancy on rilpivirine pharmacokinetics is largely unknown.MethodsInternational Maternal Pediatric Adolescent AIDS Clinical Trials P1026s is a multicenter, nonblinded, prospective study evaluating antiretroviral pharmacokinetics in HIV-infected pregnant women that included a cohort receiving rilpivirine 25 mg once daily as part of their combination antiretrovirals for clinical care. Thirty-two women were enrolled in this study. Intensive pharmacokinetic sampling was performed at steady state during the second trimester, the third trimester, and postpartum. Maternal and umbilical cord blood samples were obtained at delivery. Plasma rilpivirine concentration was measured using liquid chromatography-mass spectrometry; lower limit of quantitation was 10 ng/mL.ResultsMedian (range) AUC0-24 were 1969 (867-4987, n = 15), 1669 (556-4312, n = 28), and 2387 (188-6736, n = 28) ng·h/mL in the second trimester, the third trimester, and postpartum, respectively (P < 0.05 for either trimester vs postpartum). Median (range) C24 were 63 (37-225, n = 17), 56 (

Blumea balsamifera (L.) DC is a medicinal plant widely used against various ailments throughout Asian and African cultures. The reported efficacy of B. balsamifera and its phytochemicals against respiratory disorders suggests that it can be a potential therapeutic against the coronavirus disease 2019 (COVID-19), which is also a respiratory disease. This potential was demonstrated through an in silico assessment utilizing B. balsamifera phytochemicals and targeting the severe acute respiratory syndrome-coronavirus-2 main protease (SARS-CoV-2 Mpro), an enzyme that plays an important role in the infection process by SARS-CoV-2. The general strategy implemented was termed phytochemical mining in tandem with virtual screening (PM-VS). Data gathering of B. balsamifera phytochemicals reported in the literature was first conducted (PM stage) followed by VS through automated molecular docking of multiple ligands. The present study obtained the most comprehensive phytochemical record and organization of B. balsamifera phytochemicals (a total of 331). Surprisingly, 113 of the unique phytochemicals were promising SARS-CoV-2 Mpro inhibitors, of which 12 were re-discovered antiviral drugs from the plant. The promising inhibitors also reveal interesting in silico drug absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. Further analysis of the promising phytochemicals and their interactions with SARS-CoV-2 Mpro hints at the phenylpropanoid moiety (Ph-C3-) as a potential pharmacophore of the target enzyme. This study illustrated the utility of PM-VS in the preliminary stages of drug discovery and development; however, further studies (e.g. exhaustive VS and definitive "ex silico" experiments) are needed to confirm the present finding. [ABSTRACT FROM AUTHOR]

People living with HIV (PLWH) have a higher prevalence of respiratory symptoms than people without human immunodeficiency virus (HIV). Antiretroviral therapy has been associated with worsened airflow limitation. This cross-sectional study assessed respiratory health impairment among PLWH and its association with protease inhibitor use using data from Multicenter AIDS Cohort Study visits between April 1, 2017 and March 31, 2018. Participants completed the St. George's Respiratory Questionnaire (SGRQ), modified Medical Research Council (mMRC) dyspnea scale, spirometry, and diffusion capacity measurement. Visit data were compared among PI users, non-PI users, and men without HIV. Binary and ordinal logistic models were used to determine the associations between HIV status, PI use, and covariates with primary outcomes of dichotomized SGRQ and mMRC dyspnea scores. Of PI users, 57/177 (32.2%) self-reported pulmonary disease compared with 132/501 (26.4%) of non-PI users and 105/547 (19.2%) men without HIV. Of PI users, 77/177 (45.3%) had SGRQ scores ≥10, while 171/501 (34.7%) of non-PI users and 162/549 (29.9%) of people living without HIV had SGRQ scores ≥10 (p = .001). Adjusted models found an association between PI use and SGRQ score ≥10 [odds ratio (OR) 1.91 (95% confidence interval [CI] 1.29–2.82), ref: HIV negative and OR 1.50 (95% CI 1.01–2.22) ref: non-PI users]. A similar association was found with mMRC scores and PI use [OR 1.79 (95% CI 1.21–2.64), ref: HIV negative and OR 1.53 (95% CI 1.04–2.25), ref: non-PI users]. PI use is associated with worse respiratory health status, increased dyspnea, and an increased prevalence of self-reported pulmonary disease. [ABSTRACT FROM AUTHOR]

The article offers information on production method of Tenofovir disoproxil fumarate. It mentions Tenofovir disoproxil fumarate should be kept in a tightly closed container, protected from light and stored at a temperature between 2–8 degree celsius; and also mentions Tenofovir disoproxil fumarate may exhibit polymorphism.

Abstract Background The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in millions of infections worldwide. While the search for an effective antiviral is still ongoing, experimental therapies based on repurposing of available antivirals is being attempted, of which HIV protease inhibitors (PIs) have gained considerable interest. Inhibition profiling of the PIs directly against the viral protease has never been attempted in vitro, and while few studies reported an efficacy of lopinavir and ritonavir in SARS-CoV-2 context, the mechanism of action of the drugs remains to be validated. Methods We carried out an in-depth analysis of the efficacy of HIV PIs against the main protease of SARS-CoV-2 (Mpro) in cell culture and in vitro enzymatic assays, using a methodology that enabled us to focus solely on any potential inhibitory effects of the inhibitors against the viral protease. For cell culture experiments a dark-to-bright GFP reporter substrate system was designed. Results Lopinavir, ritonavir, darunavir, saquinavir, and atazanavir were able to inhibit the viral protease in cell culture, albeit in concentrations much higher than their achievable plasma levels, given their current drug formulations. While inhibition by lopinavir was attributed to its cytotoxicity, ritonavir was the most effective of the panel, with IC50 of 13.7 µM. None of the inhibitors showed significant inhibition of SARS-CoV-2 Mpro in our in vitro enzymatic assays up to 100 µM concentration. Conclusion Targeting of SARS-CoV-2 Mpro by some of the HIV PIs might be of limited clinical potential, given the high concentration of the drugs required to achieve significant inhibition. Therefore, given their weak inhibition of the viral protease, any potential beneficial effect of the PIs in COVID-19 context might perhaps be attributed to acting on other molecular target(s), rather than SARS-CoV-2 Mpro.