Dimeric Macrocyclic Polyamines with Potent Inhibitory Activity against Human Immunodeficiency Virus

1995 ◽  
Vol 6 (5) ◽  
pp. 337-344 ◽  
Author(s):  
Y. Inouye ◽  
T. Kanamori ◽  
M. Sugiyama ◽  
T. Yoshida ◽  
T. Koike ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Cytopathic Effect ◽  
Syncytium Formation ◽  
Physiological Conditions ◽  
Structure Activity ◽  
Immunodeficiency Virus ◽  
Macrocyclic Polyamines ◽  
Anti Hiv ◽  
Viral Cytopathic Effect ◽  
Potent Inhibitory Activity

The structure-activity relationships of monomeric and dimeric macrocyclic polyamines were studied in an attempt to find potent inhibitors of human immunodeficiency virus (HIV) types 1 and 2. In general, dimeric polyamines are superior as HIV inhibitors to their monomeric counterparts, and the activity of a dimer is proportional to that of its constituent monomers. For the monomeric compounds, the amount of positive charge on the monomer rings under physiological conditions was more important for anti-HIV activity than the ring size. On the basis of these findings, the 14-membered tetraamine cyclam was selected as the component of dimeric compounds with potentially high activity. Of the series of newly synthesized bicyclams, in which the monomeric cyclams were linked at each C-6 position, a compound with an aIkyI chain bridge three carbons in length was found to exhibit the maximum anti-HIV activity. For one particular strain (HIV-2GH-1), syncytium formation was inhibited by the bicyclams at a similar concentration to that required to inhibit the viral cytopathic effect.

scholarly journals Anti-Human Immunodeficiency Virus Activity of YK-FH312 (a Betulinic Acid Derivative), a Novel Compound Blocking Viral Maturation

2001 ◽  
Vol 45 (4) ◽  
pp. 1225-1230 ◽  
Author(s):  
Taisei Kanamoto ◽  
Yoshiki Kashiwada ◽  
Kenji Kanbara ◽  
Kazuyo Gotoh ◽  
Manabu Yoshimori ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Betulinic Acid ◽  
Electron Microscopic Observation ◽  
Syncytium Formation ◽  
Inhibition Assay ◽  
Hiv Replication ◽  
Electron Microscopic ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT Betulinic acid, a triterpenoid isolated from the methyl alcohol extract of the leaves of Syzigium claviflorum, was found to have a potent inhibitory activity against human immunodeficiency virus type 1 (HIV-1). Betulinic acid derivatives were synthesized to enhance the anti-HIV activity. Among the derivatives, 3-O-(3′,3′-dimethylsuccinyl) betulinic acid, designated YK-FH312, showed the highest activity against HIV-induced cytopathic effects in HIV-1-infected MT-4 cells. To determine the step(s) of HIV replication affected by YK-FH312, a syncytium formation inhibition assay in MOLT-4/HIV-1IIIB and MOLT-4 coculture, a multinuclear-activation-of-galactosidase-indicator (MAGI) assay in MAGI-CCR5 cells, electron microscopic observation, and a time-of-addition assay were performed. In the syncytium formation inhibition assay or in the MAGI assay for de novo infection, the compound did not show inhibitory effects against HIV replication. Conversely, no virions were detected in HIV-1-infected cell cultures treated with YK-FH312 either by electron microscopic observation or by viral yield in the supernatant. In accordance with a p24 enzyme-linked immunosorbent assay of culture supernatant in the time-of-addition assay, YK-FH312 inhibited virus expression in the supernatant when it was added 18 h postinfection. However, Western blot analysis of the cells in the time-of-addition assay revealed that the production of viral proteins in the cells was not inhibited completely by YK-FH312. These results suggest that YK-FH312 might affect the step(s) of virion assembly and/or budding of virions, and this is a novel mechanism of action of an anti-HIV compound.

scholarly journals Potent and Selective Inhibitors of Human Immunodeficiency Virus Protease Structurally Related to L-694,746

1998 ◽  
Vol 9 (4) ◽  
pp. 21-27
Author(s):  
P Franchetti ◽  
P Perlini ◽  
G Abu Sheikha ◽  
L Cappellacci ◽  
M Grifantini ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Cytopathic Effect ◽  
Selectivity Index ◽  
Hiv Protease ◽  
Enzyme Assays ◽  
Hiv Protease Inhibitors ◽  
Human Immunodeficiency Virus Protease ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

A series of human immunodeficiency virus (HIV) protease inhibitors, which are analogues of N-[2( R)-hydroxy-1( S)-indanyl]-5( S)-[( tert-butyloxycarbonyl)amino]-4( S)-hydroxy-6-phenyl-2-( R)-[[4-(carboxymethoxy)phenyl]methyl]hexanamide (L-694,746), a metabolite of the anti-HIV agent L-689,502, were synthesized. In these compounds, the acetic group linked to the para position of the P1′ phenyl in the reference inhibitor was replaced either by the bioisosteric phosphonomethoxy group and its diisopropyl/dibenzyl derivatives, or the 1H-tetrazol-5-yl-methoxy group and its 1-benzyl derivative. In enzyme assays, phosphonomethoxy and tetrazolmethoxy analogues proved to be potent inhibitors of the HIV-1 protease, with IC50 values as low as 0.04 nM. When tested for anti-HIV-1 activity in cell-based assays, most of the new derivatives proved active, with benzyl derivatives being more active than their highly polar, unsubstituted counterparts. The dibenzylphosphonomethoxy analogue was the most active compound, with an EC50 value of 10 nM and a selectivity index of 20 000. When compounds were examined for their capability to reduce p24 levels in both acutely and chronically infected MT-4 and H9/IIIB cells, all of them were found to be active at concentrations close to those capable of preventing HIV-1-induced cytopathic effect.

scholarly journals trans-Dominant Interference with Human Immunodeficiency Virus Type 1 Replication and Transmission in CD4+ Cells by an Envelope Double Mutant

1999 ◽  
Vol 73 (10) ◽  
pp. 8290-8302 ◽  
Author(s):  
Steve S.-L. Chen ◽  
Sheau-Fen Lee ◽  
Chin-Kai Chuang ◽  
V. Samuel Raj
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Double Mutant ◽  
Syncytium Formation ◽  
Cytoplasmic Domain ◽  
Viral Infectivity ◽  
Immunodeficiency Virus ◽  
Anti Hiv

ABSTRACT We previously reported that a human immunodeficiency virus type 1 (HIV-1) envelope (Env) mutant with the whole cytoplasmic domain deleted, denoted mutant TC, is able to dominantly interfere with wild-type (wt) virus infectivity. In the present study, the feasibility of developing a dominant negative mutant-based genetic anti-HIV strategy targeting the gp41 cytoplasmic domain was investigated. Mutants TC and 427,TC, a TC derivative with a Trp-to-Ser substitution introduced into residue 427 in the CD4-binding site, and a series of mutants with deletions in the cytoplasmic domain, effectivelytrans-dominantly interfered with wt Env-mediated viral infectivity, as demonstrated by an env trans-complementation assay. The syncytium formation-defective 427,TC double mutant not only inhibited heterologous LAV and ELI Env-mediated viral infectivity but also interfered with syncytium formation and infectivity mediated by the Env proteins of the two primary isolates 92BR and 92US. Stable HeLa-CD4-LTR-β-gal clones that harbored Tat-controlled expression cassettes encoding the control ΔKS, which had a deletion in the env gene, wt, or mutantenv gene were generated. Viral transmission mediated by laboratory-adapted T-cell-tropic HXB2 and NL4-3 viruses was greatly reduced in the TC and 427,TC transfectants compared to that observed in the control ΔKS and wt transfectants. Viral replication caused by HXB2 and NL4-3 viruses and by macrophage-tropic ConB and ADA-GG viruses was delayed or reduced in human CD4+ T cells transfected with the 427,TC env construct compared to that observed in cells transfected with the control ΔKS or TC envconstruct. The lack of significant interference by TC mutant was due neither to the lack of TC env gene integration into host DNA nor to the lack of TC Env expression upon Tat induction. These results indicate that this 427,TC Env double mutant has a role in the development of trans-dominant mutant-based genetic anti-HIV strategies.

scholarly journals Profile of Resistance of Human Immunodeficiency Virus to Mannose-Specific Plant Lectins

2004 ◽  
Vol 78 (19) ◽  
pp. 10617-10627 ◽  
Author(s):  
Jan Balzarini ◽  
Kristel Van Laethem ◽  
Sigrid Hatse ◽  
Kurt Vermeire ◽  
Erik De Clercq ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Amino Acid ◽  
Syncytium Formation ◽  
Cross Resistance ◽  
Blue Green Algae ◽  
Plant Lectins ◽  
Glycosylation Sites ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT The mannose-specific plant lectins from the Amaryllidaceae family (e.g., Hippeastrum sp. hybrid and Galanthus nivalis) inhibit human immunodeficiency virus (HIV) infection of human lymphocytic cells in the higher nanogram per milliliter range and suppress syncytium formation between persistently HIV type 1 (HIV-1)-infected cells and uninfected CD4+ T cells. These lectins inhibit virus entry. When exposed to escalating concentrations of G. nivalis and Hippeastrum sp. hybrid agglutinin, a variety of HIV-1(IIIB) strains were isolated after 20 to 40 subcultivations which showed a decreased sensitivity to the plant lectins. Several amino acid changes in the envelope glycoprotein gp120, but not in gp41, of the mutant virus isolates were observed. The vast majority of the amino acid changes occurred at the N glycosylation sites and at the S or T residues that are part of the N glycosylation motif. The degree of resistance to the plant lectins was invariably correlated with an increasing number of mutated glycosylation sites in gp120. The nature of these mutations was entirely different from that of mutations that are known to appear in HIV-1 gp120 under the pressure of other viral entry inhibitors such as dextran sulfate, bicyclams (i.e., AMD3100), and chicoric acid, which also explains the lack of cross-resistance of plant lectin-resistant viruses to any other HIV inhibitor including T-20 and the blue-green algae (cyanobacteria)-derived mannose-specific cyanovirin. The plant lectins represent a well-defined class of anti-HIV (microbicidal) drugs with a novel HIV drug resistance profile different from those of other existing anti-HIV drugs.

scholarly journals Sophorolipids, Microbial Glycolipids with Anti-Human Immunodeficiency Virus and Sperm-Immobilizing Activities

2005 ◽  
Vol 49 (10) ◽  
pp. 4093-4100 ◽  
Author(s):  
Vishal Shah ◽  
Gustavo F. Doncel ◽  
Theodoros Seyoum ◽  
Kristin M. Eaton ◽  
Irina Zalenskaya ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Cytotoxic Activities ◽  
Cell Toxicity ◽  
Human Semen ◽  
Virucidal Activity ◽  
Structure Activity ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Topical Microbicide

ABSTRACT The increased incidence of human immunodeficiency virus (HIV)/AIDS disease in women aged 15 to 49 years has identified the urgent need for a female-controlled, efficacious, and safe vaginal topical microbicide. To meet this challenge, sophorolipid (SL) produced by Candida bombicola and its structural analogs have been studied in this report for their spermicidal, anti-HIV, and cytotoxic activities. The sophorolipid diacetate ethyl ester derivative is the most potent spermicidal and virucidal agent of the series of SLs studied. Its virucidal activity against HIV and sperm-immobilizing activity against human semen are similar to those of nonoxynol-9. However, it also induced enough vaginal cell toxicity to raise concerns about its applicability for long-term microbicidal contraception. Its structure-activity relationship has been established for creating new analogs with less cytotoxicity and higher activity.

Syntheses and Biological Evaluation of 5′-O-Myristoyl Derivatives of Thymidine against Human Immunodeficiency Virus

1997 ◽  
Vol 8 (5) ◽  
pp. 417-427 ◽  
Author(s):  
K Parang ◽  
LI Wiebe ◽  
EE Knaus
Keyword(s):  
Human Immunodeficiency Virus ◽  
Biological Evaluation ◽  
Log P ◽  
Moderate Activity ◽  
Porcine Liver ◽  
Activity Data ◽  
Structure Activity ◽  
Immunodeficiency Virus ◽  
Derivatives Of ◽  
Anti Hiv

A series of 5′- Oacyl derivatives of thymidine (dThd) were prepared by direct acylation of thymidine using the Mitsunobu reaction. Further reaction of the bromo analogues with sodium azide gave azido ester analogues. Anti-human immunodeficiency virus type 1 (HIV-1) activities were determined against HIV-infected T4 lymphocytes. 5′- O-(12-Azidododecanoyl)thymidine exhibited moderate activity (EC50 4.6 μM) against HIV-infected T4 lymphocytes. 5- O-(2-Bromotetradecanoyl)-thymidine was found to be the most stable ester (t1/2 15.3 min) to hydrolysis by porcine liver esterase in vitro. Partition coefficients (P) in n-octanol-phosphate buffer were determined (log10 P range 4.15–6.72) and compared with the theoretical values calculated (log10 P 3.96–6.53) using the PALLAS program. Anti-HIV structure-activity data suggest that the experimental partition coefficient should be in the log10 P 4.6–4.8 range for optimum anti-HIV activity. The structures of these thymidine analogues were optimized using molecular mechanics (MM+ force field) and semi-empirical quantum mechanics PM3 calculations. The moderately active compounds adopted a similar C-2′ endo sugar conformation and exhibited similar energies for the lowest energy conformer. A quantitative structure-activity relationship (QSAR) regression equation was developed, based on the optimized structures and anti-HIV data using the SciQSAR program, which showed that log P was a determinant of anti-HIV activity.

scholarly journals Activity of a Sulfated Polysaccharide Extracted from the Red Seaweed Aghardhiella Tenera against Human Immunodeficiency Virus and Other Enveloped Viruses

1994 ◽  
Vol 5 (5) ◽  
pp. 297-303 ◽  
Author(s):  
M. Witvrouw ◽  
J. A. Este ◽  
M. Q. Mateu ◽  
D. Reymen ◽  
G. Andrei ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Dextran Sulfate ◽  
Cytopathic Effect ◽  
Syncytium Formation ◽  
Sulfated Polysaccharide ◽  
Red Seaweed ◽  
Enveloped Viruses ◽  
Immunodeficiency Virus ◽  
Spectrum Activity ◽  
Hiv 1

A galactan sulfate (GS) was isolated from an aqueous extract of the red seaweed Aghardhiella tenera and partially purified. GS inhibited the cytopathic effect of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) in MT-4 cells at concentrations 10-fold higher than those required for the inhibition by dextran sulfate (MW 5000) of the cytopathic effect of HIV-1 and HIV-2 (50% inhibitory concentrations: 0.5 and 0.05 μg ml−1, respectively). GS suppressed syncytium formation between MOLT-4 cells and persistently HIV-1- or HIV-2-infected HUT-78 cells at concentrations higher than 5 μg ml−1. Like dextran sulfate (DS) and aurintricarboxylic acid (ATA), GS inhibited the binding of HIV-1 to the cells and the binding of anti-gp120 mAb to HIV-1 gp120. Like DS and ATA, GS proved active not only against HIV-1 and HIV-2 but also against other enveloped viruses, i.e. herpes-, toga-, arena-, myxo- and rhabdoviruses. GS represents a natural polysaccharide with broad-spectrum activity against a number of important viral pathogens.

scholarly journals Structure-Based Design of Novel Dihydroalkoxybenzyloxopyrimidine Derivatives as Potent Nonnucleoside Inhibitors of the Human Immunodeficiency Virus Reverse Transcriptase

1998 ◽  
Vol 42 (12) ◽  
pp. 3225-3233 ◽  
Author(s):  
Elise A. Sudbeck ◽  
Chen Mao ◽  
Rakesh Vig ◽  
T. K. Venkatachalam ◽  
Lisa Tuel-Ahlgren ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Mononuclear Cells ◽  
Binding Pocket ◽  
Hiv Reverse Transcriptase ◽  
Hiv Replication ◽  
Peripheral Blood Mononuclear ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Potent Inhibitory Activity

ABSTRACT Two highly potent dihydroalkoxybenzyloxopyrimidine (DABO) derivatives targeting the nonnucleoside inhibitor (NNI) binding site of human immunodeficiency virus (HIV) reverse transcriptase (RT) have been designed based on the structure of the NNI binding pocket and tested for anti-HIV activity. Our lead DABO derivative, 5-isopropyl-2-[(methylthiomethyl)thio]-6-(benzyl)-pyrimidin-4-(1H)-one, elicited potent inhibitory activity against purified recombinant HIV RT and abrogated HIV replication in peripheral blood mononuclear cells at nanomolar concentrations (50% inhibitory concentration, <1 nM) but showed no detectable cytotoxicity at concentrations as high as 100 μM.

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