Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Enfuvirtide (also known as Fuzeon, T-20, or DP-178) is an antiretroviral fusion inhibitor which prevents human immunodeficiency virus type 1 (HIV-1) from entering host cells. This linear 36-mer synthetic peptide is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1-infected individuals and AIDS patients with multidrug-resistant HIV infections. Although enfuvirtide is an efficient anti-HIV-1 drug, its clinical use is limited by a short plasma half-life, i.e., approximately 2 h, which requires twice-daily subcutaneous injections, often resulting in skin sensitivity reaction side effects at the injection sites. Ultimately, 80% of patients stop enfuvirtide treatment within 6 months because of these side effects. We report on the development of long-lasting enfuvirtide conjugates by the use of the site-specific conjugation of enfuvirtide to an antithrombin-binding carrier pentasaccharide (CP) through polyethylene glycol (PEG) linkers of various lengths. These conjugates showed consistent and broad anti-HIV-1 activity in the nanomolar range. The coupling of the CP to enfuvirtide only moderately affected the in vitro anti-HIV-1 activity in the presence of antithrombin. Most importantly, one of these conjugates, enfuvirtide-PEG(12)-CP (EP40111), exhibited a prolonged elimination half-life of more than 10 h in rat plasma compared to the half-life of native enfuvirtide, which was 2.8 h. On the basis of the pharmacokinetic properties of antithrombin-binding pentasaccharides, the anticipated half-life of EP40111 in humans would putatively be about 120 h, which would allow subcutaneous injection once a week instead of twice daily. In conclusion, EP40111 is a promising compound with strong potency as a novel long-lasting anti-HIV-1 drug.
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PMID:Long-lasting enfuvirtide carrier pentasaccharide conjugates with potent anti-human immunodeficiency virus type 1 activity. 1980 67

Viruses need to deliver their genomic information into the host cell lumen to establish productive infection. Enveloped viruses accomplish this task by fusing their membrane with a host cell membrane. Membrane fusion is facilitated by specialized viral membrane proteins, which mediate binding and entry into host cells. The architecture of the fusion machinery of envelope proteins can differ between viruses, and class I, II and III fusion systems have been described. However, the conformational rearrangements associated with membrane fusion are comparable and constitute attractive targets for intervention. The fusion apparatus of the human immunodeficiency virus (HIV) envelope protein (Env), a class I fusion protein, is located in the transmembrane unit gP41 of Env. The fusion machinery is activated by Env binding to CD4 and a chemokine coreceptor, and the structural rearrangements in gp41 associated with membrane fusion comprise the insertion of a fusion peptide into the target cell membrane and the formation of a stable six-helix bundle structure. These processes can be efficiently inhibited by peptides mimicking conserved functional elements in gp41. A prominent example for such peptides, termed fusion inhibitors, is the peptide T-20 (enfuvirtide, Fuzeon) which is used as salvage therapy of HIV/AIDS. Here, we will discuss how HIV mediates fusion with host cell membranes and how this process can be blocked by peptides targeting gp41. In addition, we will discuss peptide inhibitors of other class I viral fusion proteins.
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PMID:Peptide-based inhibitors of the HIV envelope protein and other class I viral fusion proteins. 2003 Jun 13

The pharmacologic utility of lengthy peptides can be hindered by loss of bioactive structure and rapid proteolysis, which limits bioavailability. For example, enfuvirtide (Fuzeon, T20, DP178), a 36-amino acid peptide that inhibits human immunodeficiency virus type 1 (HIV-1) infection by effectively targeting the viral fusion apparatus, has been relegated to a salvage treatment option mostly due to poor in vivo stability and lack of oral bioavailability. To overcome the proteolytic shortcomings of long peptides as therapeutics, we examined the biophysical, biological, and pharmacologic impact of inserting all-hydrocarbon staples into an HIV-1 fusion inhibitor. We find that peptide double-stapling confers striking protease resistance that translates into markedly improved pharmacokinetic properties, including oral absorption. We determined that the hydrocarbon staples create a proteolytic shield by combining reinforcement of overall alpha-helical structure, which slows the kinetics of proteolysis, with complete blockade of peptide cleavage at constrained sites in the immediate vicinity of the staple. Importantly, double-stapling also optimizes the antiviral activity of HIV-1 fusion peptides and the antiproteolytic feature extends to other therapeutic peptide templates, such as the diabetes drug exenatide (Byetta). Thus, hydrocarbon double-stapling may unlock the therapeutic potential of natural bioactive polypeptides by transforming them into structurally fortified agents with enhanced bioavailability.
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PMID:Hydrocarbon double-stapling remedies the proteolytic instability of a lengthy peptide therapeutic. 2066 Mar 16

The envelope glycoprotein complex (Env) is responsible for entry of the human immunodeficiency virus type 1 (HIV-1) into cells by mediating attachment to target cells and subsequent membrane fusion. Env consists of three gp120 subunits that mediate receptor and co-receptor attachment and three gp41 subunits responsible for membrane fusion. Several steps of the entry process can serve as drug targets. Receptor antagonists prevent attachment of gp120 to the receptor or co-receptor and conformational changes within gp41 required for membrane fusion can be inhibited by fusion inhibitors. Enfuvirtide (T20, Fuzeon) is a peptide based on the gp41 sequence and is the only approved fusion inhibitor. It prevents membrane fusion by competitively binding to gp41 and blocking the formation of the post-fusion structure. New generations of T20-like peptides have been developed with improved potency and stability. Besides T20 and derivatives, other fusion inhibitors have been developed that target different domains of gp41. Here we discuss the development of fusion inhibitors, their mode of action and their potential for incorporation in future drug regimens.
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PMID:Inhibition of HIV-1 by fusion inhibitors. 2112 87

Enveloped viruses penetrate their cell targets following the merging of their membrane with that of the cell. This fusion process is catalyzed by one or several viral glycoproteins incorporated on the membrane of the virus. These envelope glycoproteins (EnvGP) evolved in order to combine two features. First, they acquired a domain to bind to a specific cellular protein, named "receptor." Second, they developed, with the help of cellular proteins, a function of finely controlled fusion to optimize the replication and preserve the integrity of the cell, specific to the genus of the virus. Following the activation of the EnvGP either by binding to their receptors and/or sometimes the acid pH of the endosomes, many changes of conformation permit ultimately the action of a specific hydrophobic domain, the fusion peptide, which destabilizes the cell membrane and leads to the opening of the lipidic membrane. The comprehension of these mechanisms is essential to develop medicines of the therapeutic class of entry inhibitor like enfuvirtide (Fuzeon) against human immunodeficiency virus (HIV). In this chapter, we will summarize the different envelope glycoprotein structures that viruses develop to achieve membrane fusion and the entry of the virus. We will describe the different entry pathways and cellular proteins that viruses have subverted to allow infection of the cell and the receptors that are used. Finally, we will illustrate more precisely the recent discoveries that have been made within the field of the entry process, with a focus on the use of pseudoparticles. These pseudoparticles are suitable for high-throughput screenings that help in the development of natural or artificial inhibitors as new therapeutics of the class of entry inhibitors.
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PMID:Cell entry of enveloped viruses. 2131 Feb 96

The viral peptide fusion inhibitor Fuzeon (T-20/DP178/enfuvirtide) is an essential part of the drug combination that has significantly increased the quality of life and life span of many acquired immuno-deficiency syndrome (AIDS) patients. Its development as a drug preceded the elucidation of its precise inhibitory mechanism, as well as its molecular targets. The initial model was that Fuzeon inhibits human immunodeficiency virus (HIV) entry by targeting one site within the viral transmembrane envelope protein. Herein, we describe the emerging discoveries that extend this model towards a multifaceted mechanism for the drug in targeting HIV. This significantly advances the understanding of how viruses enter host cells and opens a new window of opportunity for designing future viral fusion inhibitors.
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PMID:Multifaceted action of Fuzeon as virus-cell membrane fusion inhibitor. 2176 76

The emergence of drug-resistant strains of influenza virus has catalysed a search for new antiviral agents to supplement or replace existing drugs. Following the success of the human immunodeficiency virus entry blocker Enfuvirtide, there has been a resurgence of interest in peptide-based antivirals. In this paper, we report on the discovery of a novel family of peptides (FluPep, FP) that function as inhibitors of influenza A virus infection. The prototype peptide (FP1, also known as Tkip) interacts with haemagglutinin and inhibits the binding of the virus to cell membranes. Using a plaque-reduction assay, we have demonstrated that a variety of influenza A virus subtypes (including H1N1, H3N2 and H5N1) are inhibited by FluPep and its derivatives at nanomolar concentrations. By truncating FluPep we have identified a minimal sequence of 6 aa that binds to haemagglutinin and inhibits infection. Using a mouse model of intranasal influenza virus infection, we observed potent inhibition of virus infection when peptide is given at the time of virus administration. These data indicate that FluPep is a highly effective anti-influenza agent with the potential to translate to the clinic.
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PMID:A novel family of peptides with potent activity against influenza A viruses. 2225 59

Entry of human immunodeficiency virus type 1 (HIV-1) into cells is mediated by attachment of the envelope glycoproteins, gp120 and gp41, to the CD4 receptor and a chemokine receptor (CCR5 or CXCR4) and subsequent fusion of viral and cellular membranes. Several steps of the entry process can be targeted by drugs. Receptor antagonists prevent virus attachment and fusion inhibitors block conformational changes that are required for membrane fusion. The T20 peptide (Enfuvirtide, Fuzeon), which is homologous to part of the gp41-encoded fusion machinery, is the only clinically approved fusion inhibitor, but over the last decade new generations of T20-like peptides have been developed with improved potency and stability, as well as fusion inhibitors that target alternative gp41 domains. Here, we will review the field of HIV-1 fusion inhibitors.
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PMID:Is there a future for antiviral fusion inhibitors? 2244 Sep 66

Covalent inhibitors form covalent adducts with their target, thus permanently inhibiting a physiological process. Peptide fusion inhibitors, such as T20 (Fuzeon, enfuvirtide) and C34, interact with the N-terminal heptad repeat of human immunodeficiency virus type 1 (HIV-1) gp41 glycoprotein to form an inactive hetero six-helix bundle (6-HB) to prevent HIV-1 infection of host cells. A covalent strategy was applied to peptide fusion inhibitor design by introducing a thioester group into C34-like peptide. The modified peptide maintains the specific interaction with its target N36. After the 6-HB formation, a covalent bond between C- and N-peptides was formed by an inter-helical acyl transfer reaction, as characterized by various biophysical and biochemical methods. The covalent reaction between the reactive C-peptide fusion inhibitor and its N-peptide target is highly selective, and the reaction greatly increases the thermostability of the 6-HB. The modified peptide maintains high potency against HIV-1-mediated cell-cell fusion and infection.
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PMID:Covalent fusion inhibitors targeting HIV-1 gp41 deep pocket. 2296 35

Enfuvirtide belongs to a newer class of antiretroviral (ARV) agents called fusion inhibitors for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Enfuvirtide blocks attachment, binding, and entry of the viral capsid into the host CD4+ cell. Administration is only available subcutaneously in a twice-daily regimen particularly for those patients who have previously failed more than one ARV regimen. Common side effects of enfuvirtide administration include fatigue, insomnia, nausea, and diarrhea; however, injection-site reactions are the most common side effect and present in nearly all individuals undergoing treatment. The spectrum of cutaneous manifestations ranges from little to no reaction to cysts, nodules, induration, or sclerodermalike lesions. These reactions are mostly variants of iatrogenically induced hypersensitivity and are self-limited.
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PMID:Enfuvirtide and cutaneous injection-site reactions. 2313 96


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