scholarly journals Ingenol Derivatives are Highly Potent and Selective Inhibitors of HIV Replication in Vitro

1996 ◽  
Vol 7 (5) ◽  
pp. 230-236 ◽  
Author(s):  
M. Fujiwara ◽  
K. Ijichi ◽  
K. Tokuhisa ◽  
K. Katsuura ◽  
G.-Y.-S. Wang ◽  
...  
Keyword(s):  
Syncytium Formation ◽  
Selective Inhibitor ◽  
Host Cells ◽  
Hiv Replication ◽  
Virus Adsorption ◽  
Mechanism Of Inhibition ◽  
Anti Hiv Agents ◽  
Anti Hiv

Ingenol 3,5,20-triacetate has recently been identified as a highly potent and selective inhibitor of HIV replication in vitro. To evaluate the potential of ingenol derivatives as anti-HIV agents, several ingenol derivatives have been synthesized and investigated for their anti-HIV activities, structure-activity relationships, and possible mechanisms of action. Among the ingenol derivatives, 13-hydroxyingenol-3-(2,3-dimethylbutanoate)-13-dodecanoate (RD4-2138) proved to be a highly potent and selective inhibitor of HIV replication. Its 50% effective concentration for viral replication in MT-4 cells was 0.07-0.5 nM depending on viral strains, including HIV-2. This concentration was approximately 105-fold lower than its cytotoxic threshold. RD4-2138 was also inhibitory to the syncytium formation induced by cocultivation of Molt-4 cells with Molt-4/IIIB cells (Molt-4 cells chronically infected with HIV-1). Some correlation was observed with the ingenol derivatives between their inhibitory effects on HTLV-IIIB replication and surface CD4 expression in MT-4 cells, suggesting that the mechanism of inhibition is in part attributed to the inhibition of virus adsorption through down-regulation of CD4 molecules in the host cells. However, such correlation was not identified between the inhibition of HTLV-IIIB and the activation of protein kinase C. Thus, they might have a potential as effective anti-HIV agents when toxicity in vivo could be elucidated.

scholarly journals Mechanism of selective inhibition of human immunodeficiency virus by ingenol triacetate.

1996 ◽  
Vol 40 (1) ◽  
pp. 271-273 ◽  
Author(s):  
M Fujiwara ◽  
K Ijichi ◽  
K Tokuhisa ◽  
K Katsuura ◽  
S Shigeta ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Mechanism Of Action ◽  
Selective Inhibition ◽  
Selective Inhibitor ◽  
Host Cells ◽  
Hiv Replication ◽  
Mechanism Of Inhibition ◽  
Immunodeficiency Virus ◽  
Viral Adsorption

Ingenol 3,5,20-triacetate (ITA), one of the ingenol derivatives, is a selective inhibitor of human immunodeficiency virus (HIV) replication in vitro. ITA inhibited the replication of HIV strains in MT-4 cells at concentrations of 0.051 to 0.65 microM. This concentration was approximately 10(3)-fold lower than its cytotoxic threshold. The mechanism of action of ITA is primarily attributed to the inhibition of viral adsorption to the host cells, but it is distinct from the mechanism of inhibition by other adsorption inhibitors.

scholarly journals Soybean-derived Bowman-Birk Inhibitor (BBI) Inhibits HIV Replication in Macrophages

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Tong-Cui Ma ◽  
Run-Hong Zhou ◽  
Xu Wang ◽  
Jie-Liang Li ◽  
Ming Sang ◽  
...  
Keyword(s):  
Cost Effective ◽  
Peripheral Blood Monocyte ◽  
Type I ◽  
Restriction Factors ◽  
Oligoadenylate Synthetase ◽  
Hiv Replication ◽  
Inhibitory Protein ◽  
Anti Hiv

Abstract The Bowman-Birk inhibitor (BBI), a soybean-derived protease inhibitor, is known to have anti-inflammatory effect in both in vitro and in vivo systems. Macrophages play a key role in inflammation and immune activation, which is implicated in HIV disease progression. Here, we investigated the effect of BBI on HIV infection of peripheral blood monocyte-derived macrophages. We demonstrated that BBI could potently inhibit HIV replication in macrophages without cytotoxicity. Investigation of the mechanism(s) of BBI action on HIV showed that BBI induced the expression of IFN-β and multiple IFN stimulated genes (ISGs), including Myxovirus resistance protein 2 (Mx2), 2′,5′-oligoadenylate synthetase (OAS-1), Virus inhibitory protein (viperin), ISG15 and ISG56. BBI treatment of macrophages also increased the expression of several known HIV restriction factors, including APOBEC3F, APOBEC3G and tetherin. Furthermore, BBI enhanced the phosphorylation of IRF3, a key regulator of IFN-β. The inhibition of IFN-β pathway by the neutralization antibody to type I IFN receptor (Anti-IFNAR) abolished BBI-mediated induction of the anti-HIV factors and inhibition of HIV in macrophages. These findings that BBI could activate IFN-β-mediated signaling pathway, initialize the intracellular innate immunity in macrophages and potently inhibit HIV at multiple steps of viral replication cycle indicate the necessity to further investigate BBI as an alternative and cost-effective anti-HIV natural product.

Extract of Prunella Vulgaris Spikes Inhibits HIV Replication at Reverse Transcription in vitro and can Be Absorbed from Intestine in vivo

2000 ◽  
Vol 11 (2) ◽  
pp. 157-164 ◽  
Author(s):  
Seiji Kageyama ◽  
Masahiko Kurokawa ◽  
Kimiyasu Shiraki
Keyword(s):  
Oral Administration ◽  
Reverse Transcription ◽  
Dextran Sulphate ◽  
Prunella Vulgaris ◽  
Hiv Reverse Transcriptase ◽  
Hiv Replication ◽  
Anti Hiv ◽  
In Cells

It has been reported that extracts of the spike of Prunella vulgaris (PS) exhibit anti-HIV activity at the adsorption and reverse transcription stages. In this study, the actual activity of PS in cells, kinetic analysis of the inhibitory activity of PS against HIV reverse transcriptase and the feasibility of oral administration were examined. First, to clarify whether this extract shows anti-HIV activity in cells in vitro, the number of copies of proviral DNA in HIV-exposed cells was calculated. The number of copies was significantly decreased in cells cultured in the presence of PS extract, but not in the presence of dextran sulphate. The activity of PS extract in the cells was also assessed by the drug addition test, during and after HIV adsorption. PS extract and dextran sulphate suppressed HIV production to similar levels when added after HIV adsorption. However, only PS extract suppressed HIV production at the same concentration when the drugs were added during HIV adsorption. Presumably, the penetration of the PS extract into the cells was required for this activity. Secondly, fractionated PS inhibited HIV reverse transcription in a non-competitive manner. This fractionated PS kept anti-HIV activity, but inhibited HIV replication and adsorption to a lesser extent compared to dextran sulphate. Lastly, an active component(s) was detected in plasma in vivo, after injection into the intestine, which demonstrates the feasibility of oral administration dosing.

Functionalised Dendrimers: Potential Tool for Antiretroviral Therapy

2020 ◽  
Vol 16 (5) ◽  
pp. 708-722
Author(s):  
Rohini Kharwade ◽  
Sachin More ◽  
Nilesh Mahajan ◽  
Pratibha Agrawal
Keyword(s):  
Antiretroviral Therapy ◽  
Highly Active Antiretroviral Therapy ◽  
Complete Solution ◽  
Host Cells ◽  
Hiv Replication ◽  
Viral Reservoirs ◽  
Highly Active ◽  
Hiv Virus ◽  
Anti Hiv Agents ◽  
Anti Hiv

HAART (Highly Active Antiretroviral Therapy) revolutionized HIV (Human Immunodeficiency Virus) treatment upon its introduction in 1996. But, HAART has not been a complete solution for HIV infection. HIV remains viable in latent viral reservoirs even when the adequate concentration of a drug is available in the blood. Hence, nanotechnology-based delivery systems are being developed to target the HIV virus and evaluated for their safety and efficacy. Among employed nanocarriers, dendrimers are repetitively branched molecules which are an ideal carrier for developing preventive antiretroviral drug delivery system with low-level cytotoxicity and targeted action. Dendrimers with potentially active multivalent sites combine with the gp120 of HIV and CD4 receptors of the host cells and inhibit the attachment of HIV to host cells. Some of the dendrimers are capable of interfering in HIV replication. The main objective of this review is to reveal the mechanism of anti-retroviral action of different types of functionalized dendrimers in HIV. The significance of dendrimers as therapeutic agents for targeting the viral reservoirs in case of HIV was discussed. From the published literature reviewed, it can be concluded that the functionalized dendrimers are useful as anti-HIV agents and highlighting that advance studies are required for the development of more effective dendrimers based therapy which noticeably increases the anti-HIV activity.

Target Molecules and Delivery Vehicles for Anti-HIV Drugs In vitro and In vivo

2018 ◽  
Vol 24 (29) ◽  
pp. 3393-3401 ◽  
Author(s):  
Azam Bolhassani
Keyword(s):  
Drug Targeting ◽  
Immune Deficiency Syndrome ◽  
Antiretroviral Drugs ◽  
Host Cells ◽  
Target Cells ◽  
Hiv Drugs ◽  
Anti Hiv ◽  
Hiv 1

Acquired Immune Deficiency Syndrome (AIDS) is the most serious stage of Human Immunodeficiency Virus (HIV) infection. The combinatorial Anti-Retroviral Therapy (cART) is widely used in suppressing HIV-1 infection and enhancing life span of infected patients to a significant level. However, delivery of therapeutic molecules is still a major challenge in vivo. The studies showed that the anti-HIV drugs delivered via nanocarriers could be selectively accumulated in infected cells accompanied by low side effects. On the other hand, HIV-1 infection kinetics is different in macrophages and T-cells suggesting various effects of antiretroviral drugs against HIV-1 in these target cells. Current anti-HIV therapeutic studies have focused on developing drug delivery systems targeted specifically to HIV-infected host cells. Indeed, the drug targeting can significantly lead to reduce in drug toxicity, drug dose, and increase in treatment efficacy through localizing its pharmacological activity to the site of interest. This review describes development of novel drug targeting systems used in suppressing the transmission and treatment of HIV infections.

Design, Synthesis, Molecular Modeling and Anti-HIV Assay of Novel Quinazolinone Incorporated Coumarin Derivatives

2020 ◽  
Vol 18 (1) ◽  
pp. 41-51 ◽  
Author(s):  
Mahdieh Safakish ◽  
Zahra Hajimahdi ◽  
Mohammad R. Aghasadeghi ◽  
Rouhollah Vahabpour ◽  
Afshin Zarghi
Keyword(s):  
Therapeutic Index ◽  
In Vivo Studies ◽  
One Pot ◽  
Design Synthesis ◽  
Phenyl Derivative ◽  
Hiv Therapy ◽  
Anti Hiv Agents ◽  
Anti Hiv

Background: The emergence of drug-resistant viral strains has created the need for the development of novel anti-HIV agents with a diverse structure that targets key enzymes in the HIV lifecycle. Objective: Considering the pharmacophore of integrase inhibitors, one of the validated targets for anti-HIV therapy, we designed a quinazolinone incorporated coumarin scaffold to affect HIV. Method: Coumarin is a beta enol ester and also a well-known drug scaffold. Designed structures were prepared using a one-pot three-compo Results: In vitro anti-HIV and cytotoxicity assay indicated that more than half of the compounds had EC50 values lower than 50 µM. Unsubstituted phenyl derivative showed the highest activity and selectivity with an EC50 value of 5 µM and a therapeutic index of 7. Compounds were docked into the integrase active site to investigate the probable mechanism of action. Accordingly, the hydroxyl moiety of coumarin along with the carbonyl of the quinazolinone ring could function as the metal chelating group. Quinazolinone and phenyl groups interact with side chains of IN residues, as well. Conclusion: Here, a novel anti-HIV scaffold is represented for further modification and in-vivo studies.

ACIS, A Novel KepTide™, Binds to ACE-2 Receptor and Inhibits the Infection of SARS-CoV2 Virus in vitro in Primate Kidney Cells: Therapeutic Implications for COVID-19 (Preprint)

2020 ◽  
Author(s):  
Avik Sotira Scientific
Keyword(s):  
Social Life ◽  
Plaque Assay ◽  
Host Cells ◽  
Surface Glycoprotein ◽  
Crystallographic Structure ◽  
Therapeutic Implications ◽  
Biochemical Assays ◽  
Targeted Medicine

UNSTRUCTURED Coronavirus disease 2019 (COVID-19) is a severe acute respiratory syndrome (SARS) caused by a virus known as SARS-Coronavirus 2 (SARS-CoV2). Without a targeted-medicine, this disease has been causing a massive humanitarian crisis not only in terms of mortality, but also imposing a lasting damage to social life and economic progress of humankind. Therefore, an immediate therapeutic strategy needs to be intervened to mitigate this global crisis. Here, we report a novel KepTide™ (Knock-End Peptide) therapy that nullifies SARS-CoV2 infection. SARS-CoV2 employs its surface glycoprotein “spike” (S-glycoprotein) to interact with angiotensin converting enzyme-2 (ACE-2) receptor for its infection in host cells. Based on our in-silico-based homology modeling study validated with a recent X-ray crystallographic structure (PDB ID:6M0J), we have identified that a conserved motif of S-glycoprotein that intimately engages multiple hydrogen-bond (H-bond) interactions with ACE-2 enzyme. Accordingly, we designed a peptide, termed as ACIS (ACE-2 Inhibitory motif of Spike), that displayed significant affinity towards ACE-2 enzyme as confirmed by biochemical assays such as BLItz and fluorescence polarization assays. Interestingly, more than one biochemical modifications were adopted in ACIS in order to enhance the inhibitory action of ACIS and hence called as KEpTide™. Consequently, a monolayer invasion assay, plaque assay and dual immunofluorescence analysis further revealed that KEpTide™ efficiently mitigated the infection of SARS-CoV2 in vitro in VERO E6 cells. Finally, evaluating the relative abundance of ACIS in lungs and the potential side-effects in vivo in mice, our current study discovers a novel KepTide™ therapy that is safe, stable, and robust to attenuate the infection of SARS-CoV2 virus if administered intranasally. INTERNATIONAL REGISTERED REPORT RR2-https://doi.org/10.1101/2020.10.13.337584

scholarly journals Effective decellularisation of human saphenous veins for biocompatible arterial tissue engineering applications: Bench optimisation and feasibility in vivo testing

2021 ◽  
Vol 12 ◽  
pp. 204173142098752
Author(s):  
Nadiah S Sulaiman ◽  
Andrew R Bond ◽  
Vito D Bruno ◽  
John Joseph ◽  
Jason L Johnson ◽  
...  
Keyword(s):  
Tissue Engineering ◽  
Mechanical Strength ◽  
Vascular Tissue ◽  
Sodium Dodecyl ◽  
Host Cells ◽  
Replacement Model ◽  
In Vivo Testing ◽  
Vascular Scaffolds

Human saphenous vein (hSV) and synthetic grafts are commonly used conduits in vascular grafting, despite high failure rates. Decellularising hSVs (D-hSVs) to produce vascular scaffolds might be an effective alternative. We assessed the effectiveness of a detergent-based method using 0% to 1% sodium dodecyl sulphate (SDS) to decellularise hSV. Decellularisation effectiveness was measured in vitro by nuclear counting, DNA content, residual cell viability, extracellular matrix integrity and mechanical strength. Cytotoxicity was assessed on human and porcine cells. The most effective SDS concentration was used to prepare D-hSV grafts that underwent preliminary in vivo testing using a porcine carotid artery replacement model. Effective decellularisation was achieved with 0.01% SDS, and D-hSVs were biocompatible after seeding. In vivo xeno-transplantation confirmed excellent mechanical strength and biocompatibility with recruitment of host cells without mechanical failure, and a 50% patency rate at 4-weeks. We have developed a simple biocompatible methodology to effectively decellularise hSVs. This could enhance vascular tissue engineering toward future clinical applications.

scholarly journals Lipoproteins Are Responsible for the Pro-Inflammatory Property of Staphylococcus aureus Extracellular Vesicles

2021 ◽  
Vol 22 (13) ◽  
pp. 7099
Author(s):  
Pradeep Kumar Kopparapu ◽  
Meghshree Deshmukh ◽  
Zhicheng Hu ◽  
Majd Mohammad ◽  
Marco Maugeri ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Inflammatory Responses ◽  
Surface Proteins ◽  
Host Cells ◽  
Immune Stimulation ◽  
Domains Of Life ◽  
Major Surface ◽  
Staphylococcal Aureus

Staphylococcal aureus (S. aureus), a Gram-positive bacteria, is known to cause various infections. Extracellular vesicles (EVs) are a heterogeneous array of membranous structures secreted by cells from all three domains of life, i.e., eukaryotes, bacteria, and archaea. Bacterial EVs are implied to be involved in both bacteria–bacteria and bacteria–host interactions during infections. It is still unclear how S. aureus EVs interact with host cells and induce inflammatory responses. In this study, EVs were isolated from S. aureus and mutant strains deficient in either prelipoprotein lipidation (Δlgt) or major surface proteins (ΔsrtAB). Their immunostimulatory capacities were assessed both in vitro and in vivo. We found that S. aureus EVs induced pro-inflammatory responses both in vitro and in vivo. However, this activity was dependent on lipidated lipoproteins (Lpp), since EVs isolated from the Δlgt showed no stimulation. On the other hand, EVs isolated from the ΔsrtAB mutant showed full immune stimulation, indicating the cell wall anchoring of surface proteins did not play a role in immune stimulation. The immune stimulation of S. aureus EVs was mediated mainly by monocytes/macrophages and was TLR2 dependent. In this study, we demonstrated that not only free Lpp but also EV-imbedded Lpp had high pro-inflammatory activity.

scholarly journals Lankesterella (Apicomplexa, Lankesterellidae) Blood Parasites of Passeriform Birds: Prevalence, Molecular and Morphological Characterization, with Notes on Sporozoite Persistence In Vivo and Development In Vitro

Animals ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 1451
Author(s):  
Carolina Romeiro Fernandes Chagas ◽  
Josef Harl ◽  
Vytautas Preikša ◽  
Dovilė Bukauskaitė ◽  
Mikas Ilgūnas ◽  
...  
Keyword(s):  
Morphological Characterization ◽  
Life Cycles ◽  
Diagnostic Methods ◽  
Host Cells ◽  
Blood Parasites ◽  
Serinus Canaria ◽  
Long Time ◽  
Development In Vitro

Recent studies confirmed that some Hepatozoon-like blood parasites (Apicomplexa) of birds are closely related to the amphibian parasite Lankesterella minima. Little is known about the biology of these pathogens in birds, including their distribution, life cycles, specificity, vectors, and molecular characterization. Using blood samples of 641 birds from 16 species, we (i) determined the prevalence and molecular diversity of Lankesterella parasites in naturally infected birds; (ii) investigated the development of Lankesterella kabeeni in laboratory-reared mosquitoes, Culex pipiens forma molestus and Aedes aegypti; and (iii) tested experimentally the susceptibility of domestic canaries, Serinus canaria, to this parasite. This study combined molecular and morphological diagnostic methods and determined 11% prevalence of Lankesterella parasites in Acrocephalidae birds; 16 Lankesterella lineages with a certain degree of host specificity and two new species (Lankesterella vacuolata n. sp. and Lankesterella macrovacuolata n. sp.) were found and characterized. Lankesterella kabeeni (formerly Hepatozoon kabeeni) was re-described. Serinus canaria were resistant after various experimental exposures. Lankesterella sporozoites rapidly escaped from host cells in vitro. Sporozoites persisted for a long time in infected mosquitoes (up to 42 days post exposure). Our study demonstrated a high diversity of Lankesterella parasites in birds, and showed that several avian Hepatozoon-like parasites, in fact, belong to Lankesterella genus.

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