scholarly journals Long-Acting HIV-1 Fusion Inhibitory Peptides and their Mechanisms of Action

Viruses ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 811 ◽  
Author(s):  
Chen Wang ◽  
Shuihong Cheng ◽  
Yuanyuan Zhang ◽  
Yibo Ding ◽  
Huihui Chong ◽  
...  
Keyword(s):  
Half Life ◽  
Mechanisms Of Action ◽  
Effective Concentration ◽  
Fusion Inhibitor ◽  
Inhibitory Peptides ◽  
Long Acting ◽  
Peg Chain Length ◽  
Plasma Half Life ◽  
Anti Hiv ◽  
Hiv 1

The clinical application of HIV fusion inhibitor, enfuvirtide (T20), was limited mainly because of its short half-life. Here we designed and synthesized two PEGylated C34 peptides, PEG2kC34 and PEG5kC34, with the PEG chain length of 2 and 5 kDa, respectively, and evaluated their anti-HIV-1 activity and mechanisms of action. We found that these two PEGylated peptides could bind to the HIV-1 peptide N36 to form high affinity complexes with high α-helicity. The peptides PEG2kC34 and PEG5kC34 effectively inhibited HIV-1 Env-mediated cell–cell fusion with an effective concentration for 50% inhibition (EC50) of about 36 nM. They also inhibited infection of the laboratory-adapted HIV-1 strain NL4-3 with EC50 of about 4–5 nM, and against 47 HIV-1 clinical isolates circulating in China with mean EC50 of PEG2kC34 and PEG5kC34 of about 26 nM and 32 nM, respectively. The plasma half-life (t1/2) of PEG2kC34 and PEG5kC34 was 2.6 h and 5.1 h, respectively, and the t1/2 of PEGylated C34 was about 2.4-fold and 4.6-fold longer than C34 (~1.1 h), respectively. These findings suggest that PEGylated C34 with broad-spectrum anti-HIV-1 activity and prolonged half-life can be further developed as a peptide fusion inhibitor-based long-acting anti-HIV drug for clinical use to treat HIV-infected patients who have failed to respond to current anti-retrovirus drugs.

scholarly journals A Peptide-Based HIV-1 Fusion Inhibitor with Two Tail-Anchors and Palmitic Acid Exhibits Substantially Improved In Vitro and Ex Vivo Anti-HIV-1 Activity and Prolonged In Vivo Half-Life

Molecules ◽  
2019 ◽  
Vol 24 (6) ◽  
pp. 1134 ◽  
Author(s):  
Shan Su ◽  
Giselle Rasquinha ◽  
Lanying Du ◽  
Qian Wang ◽  
Wei Xu ◽  
...  
Keyword(s):  
Palmitic Acid ◽  
Half Life ◽  
Ex Vivo ◽  
Fusion Inhibitor ◽  
C Terminus ◽  
Further Development ◽  
Anti Hiv ◽  
Hiv 1

Enfuvirtide (T20) is the first U.S. FDA-approved HIV fusion inhibitor-based anti-HIV drug. Its clinical application is limited because of its low potency and short half-life. We previously reported that peptide HP23-E6-IDL, containing both N- and C-terminal anchor-tails, exhibited stronger potency and a better resistance profile than T20. Here we designed an analogous peptide, YIK, by introducing a mutation, T639I, and then a lipopeptide, YIK-C16, by adding palmitic acid (C16) at the C-terminus of YIK. We found that YIK-C16 was 4.4- and 3.6-fold more potent than HP23-E6-IDL and YIK against HIV-1IIIB infection and 13.3- and 10.5-fold more effective than HP23-E6-IDL and YIK against HIV-1Bal infection, respectively. Consistently, the ex vivo anti-HIV-1IIIB activity, as determined by the highest dilution-fold of the serum causing 50% inhibition of HIV-1 infection, of YIK-C16 in the sera of pretreated mice was remarkably higher than that of YIK or HP23-E6-IDL. The serum half-life (t1/2 = 5.9 h) of YIK-C16 was also significantly longer than that of YIK (t1/2 = 1.3 h) and HP23-E6-IDL (t1/2 = 1.0 h). These results suggest that the lipopeptide YIK-C16 shows promise for further development as a new anti-HIV drug with improved anti-HIV-1 activity and a prolonged half-life.

scholarly journals Characterization of Antiviral Activity of Benzamide Derivative AH0109 against HIV-1 Infection

2013 ◽  
Vol 57 (8) ◽  
pp. 3547-3554 ◽  
Author(s):  
Liyu Chen ◽  
Zhujun Ao ◽  
Kallesh Danappa Jayappa ◽  
Gary Kobinger ◽  
ShuiPing Liu ◽  
...  
Keyword(s):  
Nuclear Import ◽  
Effective Concentration ◽  
Effective Vaccine ◽  
Mechanistic Analysis ◽  
Viral Cdna ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Rapid Emergence ◽  
Infection Experiments

ABSTRACTIn the absence of an effective vaccine against HIV-1 infection, anti-HIV-1 strategies play a major role in disease control. However, the rapid emergence of drug resistance against all currently used anti-HIV-1 molecules necessitates the development of new antiviral molecules and/or strategies against HIV-1 infection. In this study, we have identified a benzamide derivative named AH0109 that exhibits potent anti-HIV-1 activity at an 50% effective concentration of 0.7 μM in HIV-1-susceptible CD4+C8166 T cells. Mechanistic analysis revealed that AH0109 significantly inhibits both HIV-1 reverse transcription and viral cDNA nuclear import. Furthermore, our infection experiments indicated that AH0109 is capable of disrupting the replication of HIV-1 strains that are resistant to the routinely used anti-HIV-1 drugs zidovudine, lamivudine, nevirapine, and raltegravir. Together, these findings provide evidence for a newly identified antiviral molecule that can potentially be developed as an anti-HIV-1 agent.

scholarly journals Identification of Novel Human Immunodeficiency Virus Type 1-Inhibitory Peptides Based on the Antimicrobial Peptide Database

2010 ◽  
Vol 54 (3) ◽  
pp. 1343-1346 ◽  
Author(s):  
Guangshun Wang ◽  
Karen M. Watson ◽  
Alan Peterkofsky ◽  
Robert W. Buckheit
Keyword(s):  
Antimicrobial Peptide ◽  
Original Sequence ◽  
Inhibitory Peptides ◽  
Peptide Database ◽  
Immunodeficiency Virus ◽  
Antiviral Peptides ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Aurein 1.2

ABSTRACT To identify novel anti-HIV-1 peptides based on the antimicrobial peptide database (APD; http://aps.unmc.edu/AP/main.php ), we have screened 30 candidates and found 11 peptides with 50% effective concentrations (EC50) of <10 μM and therapeutic indices (TI) of up to 17. Furthermore, among the eight peptides (with identical amino acid compositions but different sequences) generated by shuffling the sequence of an aurein 1.2 analog, two had a TI twice that of the original sequence. Because antiviral peptides in the database have an arginine/lysine (R/K) ratio of >1, increases in the Arg contents of amphibian maximin H5 and dermaseptin S9 peptides and the database-derived GLK-19 peptide improved the TIs. These examples demonstrate that the APD is a rich resource and a useful tool for developing novel HIV-1-inhibitory peptides.

Synthesis and in vitro anti-HIV-1 activity of a series of N-arylsulfonyl-3-propionylindoles

2016 ◽  
Vol 71 (5-6) ◽  
pp. 105-109 ◽  
Author(s):  
Zhiping Che ◽  
Yuee Tian ◽  
Zhenjie Hu ◽  
Yingwu Chen ◽  
Shengming Liu ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Therapeutic Index ◽  
Effective Concentration ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

Abstract Fifteen N-arylsulfonyl-3-propionylindoles (3a–o) were prepared and preliminarily evaluated as in vitro inhibitors of human immunodeficiency virus type-1 (HIV-1). Three compounds 3c, 3g and 3i exhibited potent anti-HIV-1 activity with effective concentration (EC50) values of 0.8, 4.0 and 1.2 μg/mL, and therapeutic index (TI) values of 11.7, 16.6 and 84.1, respectively. N-(m-Nitro)phenylsulfonyl-3-propionyl-6-methylindole (3i) exhibited the most promising and best activity against HIV-1 replication. The cytotoxicity of these compounds was assessed as well.

scholarly journals Design of Novel HIV-1/2 Fusion Inhibitors with High Therapeutic Efficacy in Rhesus Monkey Models

2018 ◽  
Vol 92 (16) ◽  
Author(s):  
Huihui Chong ◽  
Jing Xue ◽  
Yuanmei Zhu ◽  
Zhe Cong ◽  
Ting Chen ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Ex Vivo ◽  
Fusion Inhibitor ◽  
Infected Monkey ◽  
Viral Loads ◽  
Fusion Inhibitors ◽  
Immunodeficiency Virus ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACTT-20 (enfuvirtide) is the only approved viral fusion inhibitor that is used for the treatment of human immunodeficiency virus type 1 (HIV-1) infection; however, it has relatively low antiviral activity and easily induces drug resistance. We recently reported a T-20-based lipopeptide fusion inhibitor (LP-40) showing improved anti-HIV activity (X. Ding et al., J Virol 91:e00831-17, 2017,https://doi.org/10.1128/JVI.00831-17). In this study, we designed LP-50 and LP-51 by refining the structure and function of LP-40. The two new lipopeptides showed dramatically enhanced secondary structure and binding stability and were exceptionally potent inhibitors of HIV-1, HIV-2, simian immunodeficiency virus (SIV), and chimeric simian-human immunodeficiency virus (SHIV), with mean 50% inhibitory concentrations (IC50s) in the very low picomolar range. They also exhibited dramatically increased potencies in inhibiting a panel of T-20- and LP-40-resistant mutant viruses. In line with theirin vitrodata, LP-50 and LP-51 exhibited extremely potent and long-lastingex vivoanti-HIV activities in rhesus monkeys: serum dilution peaks that inhibited 50% of virus infection were >15,200-fold higher than those for T-20 and LP-40. Low-dose, short-term monotherapy of LP-51 could sharply reduce viral loads to undetectable levels in acutely and chronically SHIV infected monkey models. To our knowledge, LP-50 and LP-51 are the most potent and broad HIV-1/2 and SIV fusion inhibitors, which can be developed for clinical use and can serve as tools for exploration of the mechanisms of viral entry and inhibition.IMPORTANCET-20 remains the only membrane fusion inhibitor available for the treatment of viral infection, but its relatively low anti-HIV activity and genetic barrier for drug resistance have significantly limited its clinical application. Here we report two new lipopeptide-based fusion inhibitors (LP-50 and LP-51) showing extremely potent inhibitory activities against diverse HIV-1, HIV-2, SIV, and T-20-resistant variants. Promisingly, both inhibitors exhibited potent and long-lastingex vivoanti-HIV activity and could efficiently suppress viral loads to undetectable levels in SHIV-infected monkey models. We believe that LP-50 and LP-51 are the most potent and broad-spectrum fusion inhibitors known to date and thus have high potential for clinical development.

A novel peptide shows excellent anti-HIV-1 potency as a gp41 fusion inhibitor

2018 ◽  
Vol 28 (5) ◽  
pp. 910-914 ◽  
Author(s):  
Wei Liu ◽  
Xiaohong An ◽  
Jiao Wang ◽  
Xiaoguang Zhang ◽  
Jianjun Tan ◽  
...  
Keyword(s):  
Fusion Inhibitor ◽  
Anti Hiv ◽  
Hiv 1

scholarly journals Combination of long-acting HIV fusion inhibitor albuvirtide and LPV/r showed potent efficacy in HIV-1 patients

2016 ◽  
Vol 13 (1) ◽  
Author(s):  
Hongwei Zhang ◽  
Ronghua Jin ◽  
Cheng Yao ◽  
Tong Zhang ◽  
Meixia Wang ◽  
...  
Keyword(s):  
Fusion Inhibitor ◽  
Long Acting ◽  
Hiv 1
Sign in / Sign up

Export Citation Format

Share Document