anti-HIV Activity Research Articles

Sulfoglycodendrimer Therapeutics for HIV-1 and SARS-CoV-2.

Hexavalent sulfoglycodendrimers (SGDs) are synthesized as mimics of host cell heparan sulfate proteoglycans (HSPGs) to inhibit the early stages in viral binding/entry of HIV‐1 and SARS‐CoV‐2. Using an HIV neutralization assay, the most promising of the seven candidates are found to have sub‐micromolar anti‐HIV activities. Molecular dynamics simulations are separately implemented to investigate how/where the SGDs interacted with both pathogens. The simulations revealed that the SGDs: 1) develop multivalent binding with polybasic regions within and outside of the V3 loop on glycoprotein 120 (gp120) for HIV‐1, and consecutively bind with multiple gp120 subunits, and 2) interact with basic amino acids in both the angiotensin‐converting enzyme 2 (ACE2) and HSPG binding regions of the Receptor Binding Domain (RBD) from SARS‐CoV‐2. These results illustrate the considerable potential of SGDs as inhibitors in viral binding/entry of both HIV‐1 and SARS‐CoV‐2 pathogens, leading the way for further development of this class of molecules as broad‐spectrum antiviral agents.

Screening of potential anti-HIV compounds from Achyranthes aspera extracts for SARS-CoV-2: An insight from molecular docking study

Till date millions of people are already infected by the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2). Situation is getting worse day-by-day due to lack of efficient Drug or Vaccine. It is already established that few compounds of Achyranthes aspera extract have significant anti-HIV activity. Present study examines inhibitory efficiency of 8 anti-HIV compounds of A. aspera extract against SARS-Cov-2. Angiotensin converting enzyme-2 (ACE-2) of Human body, RNA-dependent RNA polymerase (RdRp) and Main protease (Mpro) of SARS-CoV-2 have been chosen as targets for this study. The binding energies and inhibition constant values of these 8 compounds have been compared with the three drugs (Chloroquine, Hydroxychloroquine and Remdesivir). Most of the compounds showed good binding energies and inhibition constant values compared to the drugs. Excretion and Toxicity (ADMET) profile also reflected that the hits from our analysis are safe. According to the molecular docking study, among these 8 anti-HIV compounds, Oleanolic acid has the highest binding affinity and low inhibition constant value with the three proteases. So, we believe that this study will help in therapeutic efforts against SARS-CoV-2.

Hybrids of Small-Molecule CD4 Mimics with Polyethylene Glycol Units as HIV Entry Inhibitors.

CD4 mimics are small molecules that inhibit the interaction of gp120 with CD4. We have developed several CD4 mimics. Herein, hybrid molecules consisting of CD4 mimics with a long alkyl chain or a PEG unit attached through a self-cleavable linker were synthesized. In anti-HIV activity, modification with a PEG unit appeared to be more suitable than modification with a long alkyl chain. Thus, hybrid molecules of CD4 mimics, with PEG units attached through an uncleavable linker, were developed and showed high anti-HIV activity and low cytotoxicity. In investigation of pharmacokinetics in a rhesus macaque, a hybrid compound had a more effective PK profile than that of the parent compound, and intramuscular injection was a more useful administration route to maintain the high blood concentration of the CD4 mimic than intravenous injection. The presented hybrid molecules of CD4 mimics with a PEG unit would be practically useful when combined with a neutralizing antibody.

Anti-Syncytium (MC99+1A2) and Anti-Bacterial Activities from Twigs and Stems of Ficus dubia

Aims: To study the anti-HIVs and anti-bacterial activity and investigate the chemical compositions of the crude extracts and isolated compounds from stems and twig of Ficus dubia.
 Methodology: Twigs and stems of Ficus dubia were collected from Si Sawat District, Kanchanaburi Province, Thailand. Bioactivity assay and phytochemical analysis of ficus dubia were processed under standard method including, anti-HIV1-RT, antibacterial activities, and CC chromatography procedures. Structures of the compound were elucidated by spectroscopic techniques.
 Results: Bioactivities assay exposed that, the hexane, ethyl acetate, and methanol extracts of Ficus dubia were verified for anti-HIV and anti-bacterial activities. The ethyl acetate and methanol extract showed evidence of anti-HIVs-1RT inhibition at 69.02 % and 69.24 %, respectively. Anti-syncytium (MC99+1A2) among evaluated all three extracts: it afforded the lowest EC50; hexane 9.65 (TI 4.39), ethyl acetate 11.15 (TI 3.84), and methanol 43.61 (TI 3.04). Moreover, an antibacterial study on extract was also performed. The antibacterial study was evaluated using nine strains (Staphylococcus aureus, Enterobacter aerogenes, Escherichia coli 0157: H7, Escherichia coli (ETEC), Escherichia coli (EPEC), Proteus mirabilis, Salmonella typhimurium, Shigella flexneri, and Vibrio cholera) by Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) method. The MeOH extract was the most effective antibacterial with a MIC in the range >0.1 mg/mL and MBC in the range >0.2 mg/mL. However, the isolated compounds from this plant had not been studied in all bioassay. Phytochemical examination of stems and twigs from Ficus dubia had directed to the isolation of four known compounds, epifriedelanol, β-sitosterol, stigmasterol, and bergapten.
 Conclusion: The crude extract of twigs and stems of Ficus fubia were specifically active toward MC99+1A2. With these results, it could be concluded that Ficus dubia may be an accomplished candidate in pill and future medicine.

Discovery of anti-cell migration activity of an anti-HIV heterocyclic compound by identification of its binding protein hnRNP M

One compound sometimes shows two biological functions, becoming important aspect of recent drug discovery. This study began with an attempt to confirm the previously reported molecular mechanism of the anti-human immunodeficiency virus (HIV) heterocyclic compound BMMP [2-(benzothiazol-2-ylmethylthio)-4-methylpyrimidine], i.e., induction of abnormal uncoating of the viral core at the post-entry step. Our mechanistic study gave results consistent with this mechanism. We further attempted to find out the molecular target of BMMP by a pulldown approach using previously synthesized biotinylated BMMP (Biotin-BMMP) and successfully identified heterogenous nuclear ribonucleoprotein M (hnRNP M) as a BMMP-binding protein. This protein was found not to be accountable for the anti-HIV activity of BMMP. As hnRNP M has been reported to promote cancer metastasis, we tested this mechanism and found that BMMP suppressed migration of the human lung carcinoma cell line A549 stimulated with transforming growth factor-β (TGF-β). Mechanistic study showed that BMMP suppressed the expression of CD44 mRNA via the regulation of hnRNP M. Furthermore, six new derivatives of BMMP were synthesized, and the patterns of their activities against HIV-1 and cell migration were not uniform, suggesting that the anti-HIV mechanism and the anti-cell migration mechanism of BMMP are independent. Taken together, the anti-cell migration activity of the anti-HIV heterocyclic compound BMMP was newly discovered by identification of its binding protein hnRNP M using a chemical biology approach.

Phosphoramidate conjugates of 3′-azido-3′-deoxythymidine glycerolipid derivatives and amino acid esters: synthesis and anti-HIV activity

We report the synthesis of phosphoramidate conjugates of 3′-azido-3′-deoxythymidine (AZT) glycerolipid derivatives and amino acid esters. For the synthesized compounds, 50% inhibition of the HIV-1 MvP-899 strain in human T lymphoid MT-4 cells is achieved at concentrations of 0.014–0.356 µM. Significantly, compound 3c (which contained ethyl ester of α-alanine) was found to be the most active with EC50 value 0.014 µM. We show that, among these glycerolipid derivatives of AZT, some compounds are less toxic than AZT, and also they possess a similar or higher selectivity index compared to AZT (SI = 11643).

Structure and Activity of Pentacyclic Triterpenes Codrugs. A Review.

Triterpenes are a wide and important group of compounds that have several promising pharmacological properties, such as hepatoprotective, anti-inflammatory, anti-HIV, antioxidant, or anticancer activities. Such potent substances can be successfully incorporated in more complex chemical systems e.g. codrugs or pro-drugs that have a better pharmacological profile. The codrug is connected with a drug formation pathway to chemically cohere at least two drug molecules to improve positive therapeutic efficiency or decrease side effects. The codrug can be cleaved in the organism to generate effective compounds previously used as substrates. This article presents an overview of codrugs that consist of pentacyclic triterpene moiety that is chosen as a basic codrug moiety due to their wide range of vital activities and another drug molecule fragment. It was found that triterpenoid codrugs are characterized by a wide range of biological activities. However, most of them have anticancer potency.

Anti-HIV and Antibacterial Activities of Novel 2-(3-Substituted-4-oxo-3,4-dihydroquinazolin-2-yl)-2,3-dihydrophthalazine-1,4-diones

In the present study, we have synthesized a series of novel 2-(3-substituted-4-oxo-3,4-dihydroquinazolin-2-yl)-2,3-dihydrophthalazine-1,4-diones by the reaction of 3-(substituted)-2-hydrazino-quinazoline-4(3H)-ones with phthalic anhydride. The starting material 3-(substituted)-2-hydrazino-quinazolin-4(3H)-ones were synthesized from various primary amines. All the synthesized compounds were screened for their antitubercular, anti-HIV and antibacterial activity against different gram positive and gram negative strains by agar dilution method. Among the test compounds, 2-(3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-2,3-dihydrophthalazine-1,4-dione (QCT7) shown most potent antibacterial activity against E. coli, and S. aureus with the MIC of 3 µg/mL. The compound QCT7 exhibited the antitubercular activity with the MIC of 25 µg/mL and anti-HIV activity with the EC50 of 43.68 µM against HIV1 and HIV2 and offers potential lead for further optimization and development to new antitubercular and anti-HIV agents. The results obtained from this study confirm that the synthesized and biologically evaluated quinazolines showed promising antimicrobial, antitubercular and anti-HIV activities and are new scaffolds for antimicrobial activity.

Design, Synthesis, Docking Study and Biological Evaluation of 4-Hydroxy-2H-benzo[e][1,2]thiazine-3-carboxamide 1,1-dioxide Derivatives as Anti-HIV Agents.

A novel series of benzothiazine-3-carboxamide 1,1-dioxide derivatives by modifying the piroxicam scaffold was designed, synthesized, and evaluated as anti-HIV agents. The 1,2-benzothiazine-3-carboxamide 1,1-dioxide scaffold consists of hydroxy and carboxamide groups as a chelating motif to form an interaction with Mg2+ ions within the integrase active site as a target. Most of the compounds displayed encouraging anti-HIV activity in a cell-based assay. Among them, compounds 13d, 13l and 13m were the most potent with EC50 values ranging from 20-25 µM and SI > 26. Docking study of compounds in integrase active site proposed that the mechanism of action of compounds might be through Mg2+ chelation within integrase active site. The lack of severe cytotoxicity and favorable anti-HIV activity of benzothiazine-3-carboxamide 1,1-dioxide derivatives support further modifications to improve the potency.

Molecular docking studies, synthesis, characterisation, and evaluation of azetidine-2-one derivative

Azetidinone derivatives were reported to possess antibacterial, antifungal, antitumor, antitubercular activity, anti-HIV, analgesic, anti-inflammatory, and ulcerogenic activity. Molecular docking has become an important process in the course of drug discovery and docking aims to predict the binding mode and binding affinity of the protein-ligand complex. AutoDock is a popular non-commercial docking program that docks a ligand to its target protein and performs well (accurate and computationally fast). The Discovery Studio Visualizer is a free viewer that can be used to open data generated by other software in the Discovery Studio product line. A new series of Aztifdine-2-one derivative were synthesized by the reaction of Schiff base((Z)-N_(4-dimethylamino) benzylidene) pyrimidine-2-amine) with chloroacetyl chloride respectively. The chemical structures of the synthesized compounds were confirmed using IR, 1H-NMR. The synthesized compounds showed mild antibacterial activity against Staphylococcus aureus and Escherichia coli. The 5NI9 protein that was extracted from the protein database website all the compounds were drawn using the Chem draw Ultra 8.0 and Biovia draw 2018. It was saved in Mol format and then converted to PDB format using the Smiles Online Translator. All the files were logged in the Cygwin toolings. The conformation by ranking was calculated. This shows whether the compound has good binding energy with the ligand and hydrogen bonding and hydrophobic binding with the receptor. From the above analysis, it showed that compound 1 showed hydrogen bonding interactions when compared to that Standard compounds Rifampicin and isoniazid which had lesser hydrogen bonding interactions. The compound 2 did not show any hydrogen bonding. This shows that the Azetidine-2-ones shows antitubercular activity with the Enoyl-acyl carrier protein (enoyl-ACP) reductase enzyme.

Review on Synthesis Route of Quinazoline Based Hybrid Derivatives

Quinazolines are amidst the most significant pharmacological compounds in natural and medicinal chemistry, with a wide variety of pharmacological things, including antifungal, antibacterial, anti-inflammatory, anti-HIV, anticancer and analgesic activity. Designing innovative quinazolines, studying possible techniques to synthesize quinazolines, examining diverse features of quinazolines and looking for prospective uses of quinazolines have all become more important in the last two decades due to their multiple possible applications. The current review paper discusses the synthesis of quinazolines using the multi-component synthetic technique that is environmentally friendly, mild and atom-efficient. The discussion is separated into sections based on the key processes used to construct quinazoline scaffolds to provide an efficient approach for a more significant grasp. The most recent references have also been taken into account. The review should prove useful in future research on quinazoline synthesis and developing a more promising synthetic technique.

Innate Immune Response Against HIV-1.

The innate immune system is comprised of both cellular and humoral players that recognise and eradicate invading pathogens. Therefore, the interplay between retroviruses and innate immunity has emerged as an important component of viral pathogenesis. HIV-1 infection in humans that results in hematologic abnormalities and immune suppression is well represented by changes in the CD4/CD8 T cell ratio and consequent cell death causing CD4 lymphopenia. The innate immune responses by mucosal barriers such as complement, DCs, macrophages, and NK cells as well as cytokine/chemokine profiles attain great importance in acute HIV-1 infection, and thus, prevent mucosal capture and transmission of HIV-1. Conversely, HIV-1 has evolved to overcome innate immune responses through RNA-mediated rapid mutations, pathogen-associated molecular patterns (PAMPs) modification, down-regulation of NK cell activity and complement receptors, resulting in increased secretion of inflammatory factors. Consequently, epithelial tissues lining up female reproductive tract express innate immune sensors including anti-microbial peptides responsible for forming primary barriers and have displayed an effective potent anti-HIV activity during phase I/II clinical trials.

Exosomes Transport Anti-Human Immunodeficiency Virus Factors from Human Cervical Epithelial Cells to Macrophages

The female reproductive tract (FRT) is a major site of HIV sexual transmission. As the outermost layer of cells in the FRT, the human cervical epithelial cells (HCEs) have direct contact with HIV or infected cells. Our early work showed that supernatant (SN) from TLR3-activated HCEs contain the antiviral factors that could potently inhibit HIV replication in macrophages. However, it remains to be determined how HCEs transport the anti-HIV factors to macrophages. This follow-up study examined the role of exosomes in HCE-mediated anti-HIV activity. We found that TLR3 activation of HCEs resulted in the release of exosomes that contained multiple IFN-stimulated genes (ISGs: ISG56, OAS1, MxA, and Mx2) and the HIV restriction microRNAs (miR-28, miR-29 family members, miR-125b, miR-150, miR-382, miR-223, miR-20a, and miR-198). The depletion of exosomes from SN of TLR3-activated HCEs diminished HCE-mediated anti-HIV activity in macrophages, indicating that HCE-derived exosomes are responsible for transporting the antiviral molecules to macrophages. These in vitro findings suggest a novel antiviral mechanism by which HCEs participate in the FRT innate immunity against HIV infection. Further in vivo studies are necessary in order to develop an exosome-based delivery system for prevention and treatment of HIV infection through sexual transmission.

A New Approach to Developing Long-Acting Injectable Formulations of Anti-HIV Drugs: Poly(Ethylene Phosphoric Acid) Block Copolymers Increase the Efficiency of Tenofovir against HIV-1 in MT-4 Cells.

Despite the world’s combined efforts, human immunodeficiency virus (HIV), the causative agent of AIDS, remains one of the world’s most serious public health challenges. High genetic variability of HIV complicates the development of anti-HIV vaccine, and there is an actual clinical need for increasing the efficiency of anti-HIV drugs in terms of targeted delivery and controlled release. Tenofovir (TFV), a nucleotide-analog reverse transcriptase inhibitor, has gained wide acceptance as a drug for pre-exposure prophylaxis or treatment of HIV infection. In our study, we explored the potential of tenofovir disoproxil (TFD) adducts with block copolymers of poly(ethylene glycol) monomethyl ether and poly(ethylene phosphoric acid) (mPEG-b-PEPA) as candidates for developing a long-acting/controlled-release formulation of TFV. Two types of mPEG-b-PEPA with numbers of ethylene phosphoric acid (EPA) fragments of 13 and 49 were synthesized by catalytic ring-opening polymerization, and used for preparing four types of adducts with TFD. Antiviral activity of [mPEG-b-PEPA]TFD or tenofovir disoproxil fumarate (TDF) was evaluated using the model of experimental HIV infection in vitro (MT-4/HIV-1IIIB). Judging by the values of the selectivity index (SI), TFD exhibited an up to 14-fold higher anti-HIV activity in the form of mPEG-b-PEPA adducts, thus demonstrating significant promise for further development of long-acting/controlled-release injectable TFV formulations.

Boesenmaxane Diterpenoids from Boesenbergia maxwellii.

Three new diterpenoids, boesenmaxanes A-C (1-3), with an unprecedented core skeleton consisting of an unusual C-C bond between C-12 and an exo-cyclic methylene C-13, were isolated from the rhizome extracts of Boesenbergia maxwellii. The structures were elucidated by analysis of spectroscopic and X-ray diffraction data. Electronic circular dichroism spectra were used to determine the absolute configuration. All the isolates were evaluated for their cytotoxic effects, anti-HIV activity, and antimicrobial activity. Boesenmaxanes A and C (1 and 3) showed significant inhibitory activity in the syncytium reduction assay, with EC50 values of 55.2 and 27.5 μM, respectively.

Design and Synthesis of Quinolizidine Derivatives as Influenza Virus and HIV-1 Inhibitors.

We have previously reported that a quinolizidine natural product, aloperine, and its analogs can inhibit influenza virus and/or HIV-1 at low μM concentrations. The main goal of this study was to further optimize aloperine for improved anti-influenza virus activity. Structural modifications have been focused on the N12 position of aloperine scaffold. Conventional chemical synthesis was used to obtain derivatives with improved antiviral activities. The anti-HIV and anti-influenza virus activities of the synthesized compounds were determined using an MT4 cell-based HIV-1 replication assay and an anti- influenza virus infection of MDCK cell assay, respectively. Aloperine derivatives can be classified into three activity groups: those that exhibit anti-HIV activity only, anti-influenza virus only, or activity against both viruses. Aloperine optimized for potent anti-influenza activity often lost anti-HIV-1 activity, and vice versa. Compound 19 inhibited influenza virus PR8 replication with an IC50 of 0.091 μM, which is approximately 160- and 60-fold more potent than aloperine and the previously reported aloperine derivative compound 3, respectively. The data suggest that aloperine is a privileged scaffold that can be modified to become a selective antiviral compound with markedly improved potency against influenza virus or HIV-1.

<p><strong>Antibacterial and anti-HIV activity of extracellular pigment from <em>Streptomyces </em>sp. S45 isolated from Sabarimala forest soil, India</strong></p>

Actinobacteria, particularly from under-studied habitats, are often endowed with diverse biological properties. In the present study, about 17 actinobacterial strains were isolated from Sabarimala forest an understudied ecosystem in Western Ghats, India and screened for their pigment producing potential. Pinkish brown soluble pigment producing Streptomyces sp. strain S45 was selected and screened for antibacterial and anti-HIV activity. The bioactivity of ethyl acetate extract of the strain S45 showed maximum zone of inhibition against Staphylococcus aureus ATCC 29213 (17.3±0.4 mm) and Bacillus cereus (15.6±0.6 mm). Also, it showed anti-HIV activity with the IC50 value of 8.75 µg/mL. The bioactive pigment isolated from the strain S45 was partially purified and characterized using UV absorption. In bio-autography, an antibacterial compound found to be active against S. aureus ATCC 29213 and its MIC values ranged between 25-1.56 µg/mL. Variables such as glucose, rhamnose, soybean meal and CaCl 2 , pH 7 and temperature 30℃ were found to influence bioactive pigment production. Potential strain S45 was identified as Streptomyces species on the basis of microscopic, cultural, physiological and 16SrRNA analysis. Results suggest that the Streptomyces sp. S45 strain explored in this study could be a promising candidate for isolation of antibacterial and anti HIV pigment.

Long-term in vivo survival of receptor-modified syngeneic T cells in patients with human immunodeficiency virus infection

AbstractTo study human immunodeficiency virus (HIV)–specific cellular immunity in vivo, we transferred syngeneic lymphocytes after ex vivo expansion and transduction with a chimeric receptor gene (CD4/CD3-ζ) between identical twins discordant for HIV infection. Single and multiple infusions of 1010 genetically modified CD8+ T cells resulted in peak fractions in the circulation of approximately 104 to 105modified cells/106 mononuclear cells at 24 to 48 hours, followed by 2- to 3-log declines by 8 weeks. In an effort to provide longer high-level persistence of the transferred cells and possibly enhance anti-HIV activity, we administered a second series of infusions in which both CD4+ and CD8+ T cells were engineered to express the chimeric receptor and were costimulated ex vivo with beads coated with anti-CD3 and anti-CD28. Sustained fractions of approximately 103 to 104 modified cells/106 total CD4+ or CD8+cells persisted for at least 1 year. Assessment of in vivo trafficking of the transferred cells by lymphoid tissue biopsies revealed the presence of modified cells in proportions equivalent to or below those in the circulation. The cell infusions were well tolerated and were not associated with substantive immunologic or virologic changes. Thus, adoptive transfer of genetically modified HIV-antigen–specific T cells was safe. Sustained survival in the circulation was achieved when modified CD4+ and CD8+ T cells were infused together after ex vivo costimulation, indicating the important role played by antigen-specific CD4+ T cells in providing “help” to cytotoxic effectors.

Emergence of Nanotechnology to Fight HIV Sexual Transmission: The Trip of G2-S16 Polyanionic Carbosilane Dendrimer to Possible Pre-Clinical Trials.

Development of new, safe, and effective microbicides to prevent human immunodeficiency virus HIV sexual transmission is needed. Unfortunately, most microbicides proved ineffective to prevent the risk of HIV-infection in clinical trials. We are working with G2-S16 polyanionic carbosilane dendrimer (PCD) as a new possible vaginal topical microbicide, based on its short reaction times, wide availability, high reproducibility, and quantitative yields of reaction. G2-S16 PCD exerts anti-HIV activity at an early stage of viral replication, by blocking gp120/CD4/CCR5 interaction, and providing a barrier against infection for long periods of time. G2-S16 PCD was stable at different pH values, as well as in the presence of seminal fluids. It maintained the anti-HIV activity against R5/X4 HIV over time, did not generate any type of drug resistance, and retained the anti-HIV effect when exposed to semen-enhanced viral infection. Importantly, G2-S16 PCD did not modify vaginal microbiota neither in vitro or in vivo. Histopathological examination did not show vaginal irritation, inflammation, lesions, or damage in the vaginal mucosa, after administration of G2-S16 PCD at different concentrations and times in female mice and rabbit animal models. Based on these promising data, G2-S16 PCD could become a good, safe, and readily available candidate to use as a topical vaginal microbicide against HIV.

Isatin Hybrids and Their Pharmacological Investigations.

Hybridization is an important strategy to design molecules that can be effectively used to treat fatal diseases known to mankind. Molecular hybrids and their pharmacological investigations aided in discovering several potent isatin (Indole 2, 3 dione) derivatives with anti-HIV, antimalarial, antitubercular, antibacterial, and anticancer activities. Indole-2,3-dione and their derivatives have diverse pharmacological properties and have a prominent role in the discovery of new drugs. To understand the various approaches for designing new molecules based on isatin nucleus analysis of various pharmacophore hybrids, spacers/linkers between pharmacophores and isatin for hybridization and their biological activities are important. This review discusses the progress in developing isatin hybrids as biologically effective agents and their crucial aspects of design and structure-activity relationships.