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.

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 Novel 4′-Substituted Stavudine Analog with Improved Anti-Human Immunodeficiency Virus Activity and Decreased Cytotoxicity

2004 ◽  
Vol 48 (5) ◽  
pp. 1640-1646 ◽  
Author(s):  
Ginger E. Dutschman ◽  
Susan P. Grill ◽  
Elizabeth A. Gullen ◽  
Kazuhiro Haraguchi ◽  
Shingo Takeda ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiviral Drug ◽  
Antiviral Effect ◽  
Immunodeficiency Virus ◽  
Delayed Toxicity ◽  
Hiv Drugs ◽  
Further Development ◽  
Anti Hiv ◽  
Better Than

ABSTRACT The antiviral drug 2′,3′-didehydro-3′-deoxythymidine (D4T; also know as stavudine and Zerit), which is used against human immunodeficiency virus (HIV), causes delayed toxicity (peripheral neuropathy) in long-term use. After examining a series of 2′,3′-didehydro-3′-deoxy-4′-substituted thymidine (4′-substituted D4T) analogs, 4′-ethynyl D4T was found to have a fivefold-better antiviral effect and to cause less cellular and mitochondrial toxicity than D4T. The antiviral activity of this compound can be reversed by dThd but not by dCyd. The compound acted synergistically with β-l-2′,3′-deoxy-3′-thiacytidine (also known as lamivudine) and β-l-2′,3′-dideoxy-2′,3′-didehydro-5-fluorocytidine (also known as elvucitabine) and additively with 2′,3′-dideoxyinosine (also known as didanosine and Videx) and 3′-azido-3′-deoxythymidine (also known as Retovir and zidovudine) against HIV. 4′-Ethynyl D4T is phosphorylated by purified human thymidine kinase 1 (TK-1) from CEM cells with a faster relative V max and a lower Km value than D4T. The efficiency of TK-1 in the phosphorylation of 4′-ethynyl D4T is fourfold better than that of D4T. While D4T is broken down by the catabolic enzyme thymidine phosphorylase, the level of breakdown of 4′-ethynyl D4T was below detection. Since 4′-ethynyl D4T has increased anti-HIV activity and decreased toxicity and interacts favorably with other currently used anti-HIV drugs, it should be considered for further development as an anti-HIV drug.

scholarly journals Antiretroviral Drugs and Risk of Chronic Alanine Aminotransferase Elevation in Human Immunodeficiency Virus (HIV)-Monoinfected Persons: The Data Collection on Adverse Events of Anti-HIV Drugs Study

2016 ◽  
Vol 3 (1) ◽  
Author(s):  
Helen Kovari ◽  
Caroline A. Sabin ◽  
Bruno Ledergerber ◽  
Lene Ryom ◽  
Peter Reiss ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Liver Enzyme ◽  
Chronic Liver ◽  
Liver Enzyme Elevation ◽  
Immunodeficiency Virus ◽  
Short And Long Term ◽  
Enzyme Elevation ◽  
Hiv Drugs ◽  
Anti Hiv

Abstract Background.  Although human immunodeficiency virus (HIV)-positive persons on antiretroviral therapy (ART) frequently have chronic liver enzyme elevation (cLEE), the underlying cause is often unclear. Methods.  Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study participants without chronic viral hepatitis were observed to the earliest of cLEE (elevated aminotransferase ≥6 months), death, last follow-up, or January 2, 2014. Antiretroviral treatment exposure was categorized as follows: no exposure and ongoing short- and long-term exposure (<2 or ≥2 years) after initiation. Association between development of cLEE and ART exposure was investigated using Poisson regression. Results.  Among 21 485 participants observed for 105 413 person-years (PY), 6368 developed cLEE (incidence 6.04/100 PY; 95% confidence interval [CI], 5.89–6.19). Chronic liver enzyme elevation was associated with short-and long-term exposure to didanosine (<2 years rate ratio [RR] = 1.29, 95% CI, 1.11–1.49; >2 years RR = 1.26, 95% CI, 1.13–1.41); stavudine (<2 years RR = 1.51, 95% CI, 1.26–1.81; >2 years RR = 1.17, 95% CI, 1.03–1.32), and tenofovir disoproxil fumarate (<2 years RR = 1.55, 95% CI, 1.40–1.72; >2 years RR = 1.18, 95% CI, 1.05–1.32), but only short-term exposure to nevirapine (<2 years RR = 1.44, 95% CI, 1.29–1.61), efavirenz (<2 years RR = 1.14, 95% CI, 1.03–1.26), emtricitabine (<2 years RR = 1.18, 95% CI, 1.04–1.33), and atazanavir (<2 years RR = 1.20, 95% CI, 1.04–1.38). Chronic liver enzyme elevation was not associated with use of lamivudine, abacavir, and other protease inhibitors. Mortality did not differ between participants with and without cLEE. Conclusions.  Although didanosine, stavudine, nevirapine, and efavirenz have been described to be hepatotoxic, we additionally observed a consistent association between tenofovir and cLEE emerging within the first 2 years after drug initiation. This novel tenofovir-cLEE signal should be further investigated.

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 Lentiviral Vectors Interfering with Virus-Induced CD4 Down-Modulation Potently Block Human Immunodeficiency Virus Type 1 Replication in Primary Lymphocytes

2004 ◽  
Vol 78 (23) ◽  
pp. 13072-13081 ◽  
Author(s):  
Hang M. Pham ◽  
Enrique R. Argañaraz ◽  
Bettina Groschel ◽  
Didier Trono ◽  
Juan Lama
Keyword(s):  
Human Immunodeficiency Virus ◽  
Lentiviral Vectors ◽  
Viral Pathogenesis ◽  
Viral Particles ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACT CD4 down-modulation is essential for the production of human immunodeficiency virus (HIV) infectious particles. Disease progression correlates with enhanced viral induced CD4 down-modulation, and a subset of long-term nonprogressors carry viruses defective in this function. Despite multiple pieces of evidence highlighting the importance of this function in viral pathogenesis in vivo, to date, HIV-induced CD4 down-modulation has not been used as a target for intervention. We describe here HIV-based vectors that deliver truncated CD4 molecules resistant to down-modulation by the viral products Nef and Vpu. Infection of cells previously transduced with these vectors proceeded normally, and viral particles were released in normal amounts. However, the infectivity of the released virions was reduced 1,000-fold. Lentiviral vectors expressing truncated CD4 molecules were efficient at blocking HIV-1 infectivity and replication in several cell lines and in CD4-positive primary lymphocytes. The findings presented here provide proof-of-principle that approaches targeting the virus-induced CD4 down-modulation may constitute the basis for novel anti-HIV therapies.

scholarly journals Structural and Functional Characterization of Membrane Fusion Inhibitors with Extremely Potent Activity against Human Immunodeficiency Virus Type 1 (HIV-1), HIV-2, and Simian Immunodeficiency Virus

2018 ◽  
Vol 92 (20) ◽  
Author(s):  
Huihui Chong ◽  
Yuanmei Zhu ◽  
Danwei Yu ◽  
Yuxian He
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Membrane Fusion ◽  
Simian Immunodeficiency Virus ◽  
Genetic Barrier ◽  
Fusion Inhibitors ◽  
Structure Activity ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACTT-20 (enfuvirtide) is the only membrane fusion inhibitor available for the treatment of viral infection; however, it has low anti-human immunodeficiency virus (anti-HIV) activity and a low genetic barrier for drug resistance. We recently reported that T-20 sequence-based lipopeptides possess extremely potentin vitroandin vivoefficacies (X. Ding, Z. Zhang, H. Chong, Y. Zhu, H. Wei, X. Wu, J. He, X. Wang, Y. He, 2017, J Virol 91:e00831-17, https://doi.org/10.1128/JVI.00831-17; H. Chong, J. Xue, Y. Zhu, Z. Cong, T. Chen, Y. Guo, Q. Wei, Y. Zhou, C. Qin, Y. He, 2018, J Virol 92:e00775-18, https://doi.org/10.1128/JVI.00775-18). Here, we focused on characterizing the structure-activity relationships of the T-20 derivatives. First, a novel lipopeptide termed LP-52 was generated with improved target-binding stability and anti-HIV activity. Second, a large panel of truncated lipopeptides was characterized, revealing a 21-amino-acid sequence core structure. Third, it was surprisingly found that the addition of the gp41 pocket-binding residues in the N terminus of the new inhibitors resulted in increased binding but decreased antiviral activities. Fourth, while LP-52 showed the most potent activity in inhibiting divergent HIV-1 subtypes, its truncated versions, such as LP-55 (25-mer) and LP-65 (24-mer), still maintained their potencies at very low picomolar concentrations; however, both the N- and C-terminal motifs of LP-52 played crucial roles in the inhibition of T-20-resistant HIV-1 mutants, HIV-2, and simian immunodeficiency virus (SIV) isolates. Fifth, we verified that LP-52 can bind to target cell membranes and human serum albumin and has low cytotoxicity and a high genetic barrier to inducing drug resistance.IMPORTANCEDevelopment of novel membrane fusion inhibitors against HIV and other enveloped viruses is highly important in terms of the peptide drug T-20, which remains the only one for clinical use, even if it is limited by large dosages and resistance. Here, we report a novel T-20 sequence-based lipopeptide showing extremely potent and broad activities against HIV-1, HIV-2, SIV, and T-20-resistant mutants, as well as an extremely high therapeutic selectivity index and genetic resistance barrier. The structure-activity relationship (SAR) of the T-20 derivatives has been comprehensively characterized, revealing a critical sequence core structure and the target sites of viral vulnerability that do not include the gp41 pocket. The results also suggest that membrane-anchored inhibitors possess unique modes of action relative to unconjugated peptides. Combined, our series studies have not only provided drug candidates for clinical development but also offered important tools to elucidate the mechanisms of viral fusion and inhibition.

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