Selective side-chain modification of cysteine and arginine residues blocks pathogenic activity of HIV-1-Tat functional peptides

Devadas, Krishnakumar; Boykins, Robert A.; Hardegen, Neil J.; Philp, Deborah; Kleinman, Hynda K.; Osa, Etin-Osa; Wang, Jiun; Clouse, Kathleen A.; Wahl, Larry M.; Hewlett, Indira; Rappaport, Jay; Yamada, Katsushi; Dhawan, Subhash

doi:10.1016/j.peptides.2005.09.013

Cited by 3 publications

(4 citation statements)

References 52 publications

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“…The conserved C-C-CC-C-C motif of Tat has a tighter cysteine spacing than ERVK CTXLP, or conotoxins. Tat toxicity and its ability to regulate gene expression centers around the use of its cysteine-rich domain [59,60]. In driving a self-promoting inflammatory environment for HIV, Tat upregulation of NF-κB relies on its cysteine-rich motif [60,61].…”

Section: Characterization Of Ervk Ctxlp a Virus-encoded Conotoxin Prmentioning

confidence: 99%

Pro-Inflammatory Signaling Upregulates a Neurotoxic Conotoxin-Like Protein Encrypted Within Human Endogenous Retrovirus-K

Curzio

Gurm

Turnbull

et al. 2020

Cells

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Motor neuron degeneration and spinal cord demyelination are hallmark pathological events in Amyotrophic Lateral Sclerosis (ALS). Endogenous retrovirus-K (ERVK) expression has an established association with ALS neuropathology, with murine modeling pointing to a role for the ERVK envelope (env) gene in disease processes. Here, we describe a novel viral protein cryptically encoded within the ERVK env transcript, which resembles two distinct cysteine-rich neurotoxic proteins: conotoxin proteins found in marine snails and the Human Immunodeficiency Virus (HIV) Tat protein. Consistent with Nuclear factor-kappa B (NF-κB)-induced retrotransposon expression, the ERVK conotoxin-like protein (CTXLP) is induced by inflammatory signaling. CTXLP is found in the nucleus, impacting innate immune gene expression and NF-κB p65 activity. Using human autopsy specimens from patients with ALS, we further showcase CTXLP expression in degenerating motor cortex and spinal cord tissues, concomitant with inflammation linked pathways, including enhancement of necroptosis marker mixed lineage kinase domain-like (MLKL) protein and oligodendrocyte maturation/myelination inhibitor Nogo-A. These findings identify CTXLP as a novel ERVK protein product, which may act as an effector in ALS neuropathology.

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Section: Characterization Of Ervk Ctxlp a Virus-encoded Conotoxin Prmentioning

confidence: 99%

Pro-Inflammatory Signaling Upregulates a Neurotoxic Conotoxin-Like Protein Encrypted Within Human Endogenous Retrovirus-K

Curzio

Gurm

Turnbull

et al. 2020

Cells

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“…TAT is a prominent member of the family of cell penetrating peptides (CPPs). − This special type of peptide, first discovered in biological systems as HIV, has the ability to penetrate cell membranes. , TAT is the trans-activating transcriptional activator protein from HIV-1, and its sequence is GRKKRRQRRRPPQ (residues 48–60) . This “arginine-rich” sequence is essential for virus replication due to its role in the transactivation of DNA transcription and is directly involved in protein–protein recognition processes and RNA binding in vivo . , The low-toxicity TAT is very effective in penetrating cell membranes and inserting various molecules into living cells and cell nuclei in a noncovalent manner. − The high concentration of arginine, or any basic positively charged amino acids, is a typical feature of the cell penetrating peptides and probably plays a role in the initial attachment of the peptide to the negatively charged cell membrane. − The ability of several CPPs to enhance delivery through skin was already examined and proved, and different mechanisms were suggested. These features make the CPP family very attractive in the field of transdermal delivery.…”

Section: Introductionmentioning

confidence: 99%

“…25 This "arginine-rich" sequence is essential for virus replication due to its role in the transactivation of DNA transcription 26 and is directly involved in protein− protein recognition processes 27 and RNA binding in vivo. 28,29 The low-toxicity TAT is very effective in penetrating cell membranes and inserting various molecules into living cells and cell nuclei in a noncovalent manner. 30−32 The high concentration of arginine, or any basic positively charged amino acids, is a typical feature of the cell penetrating peptides and probably plays a role in the initial attachment of the peptide to the negatively charged cell membrane.…”

Section: Introductionmentioning

confidence: 99%

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HIV-TAT Enhances the Transdermal Delivery of NSAID Drugs from Liquid Crystalline Mesophases

et al. 2014

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Sodium diclofenac (Na-DFC) and celecoxib (CLXB) are common nonsteroidal anti-inflammatory (NSAID) drugs which suffer from poor bioavailability and severe side effects when consumed orally, and their transdermal delivery might present important advantages. In this study, the drugs were solubilized in cubic and lamellar mesophases as transdermal delivery vehicles, and a cell-penetrating peptide, HIV-TAT (TAT), was examined as a skin penetration enhancer. SD-NMR, ATR-FTIR, and EPR measurements revealed that, in the cubic mesophase (which is rich in water content), TAT populates the aqueous cores and binds water, while in the dense lamellar system (with the lower water content) TAT is bound also to the glycerol monooleate (GMO) and increases the microviscosity and the order degree. TAT secondary structure in the cubic system was found to be a random coil while once it was embedded in the closely packed lamellar system it transforms to a more ordered compact state of β-turns arranged around the GMO headgroups. TAT remarkably increased the diffusion of Na-DFC and CLXB from the cubic systems by 6- and 9-fold enhancement, respectively. TAT effect on drug diffusion from the lamellar systems was limited to an increase of 1.3- and 1.7-fold, respectively. The dense packing and strong binding in the lamellar phase led to slow diffusion rates and slower drug release in controlled pattern. These effects of the chemical composition and vehicle geometry on drug diffusion are demonstrated with the impacts of TAT which can be specifically utilized for controlling skin delivery of drugs as required.

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Antibodies against a multiple-peptide conjugate comprising chemically modified human immunodeficiency virus type-1 functional Tat peptides inhibit infection

et al. 2007

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Selective side-chain modification of cysteine and arginine residues blocks pathogenic activity of HIV-1-Tat functional peptides

Cited by 3 publications

References 52 publications

Pro-Inflammatory Signaling Upregulates a Neurotoxic Conotoxin-Like Protein Encrypted Within Human Endogenous Retrovirus-K

Pro-Inflammatory Signaling Upregulates a Neurotoxic Conotoxin-Like Protein Encrypted Within Human Endogenous Retrovirus-K

HIV-TAT Enhances the Transdermal Delivery of NSAID Drugs from Liquid Crystalline Mesophases

Antibodies against a multiple-peptide conjugate comprising chemically modified human immunodeficiency virus type-1 functional Tat peptides inhibit infection

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