A comparative study of the solution structures of tachyplesin I and a novel anti-HIV synthetic peptide, T22 ([Tyr5,12, Lys7]-polyphemusin II), determined by nuclear magnetic resonance

Tamamura, Hirokazu; Kuroda, Masataka; Masuda, Masao; Otaka, Akira; Funakoshi, Susumu; Nakashima, Hideki; Yamamoto, Naoki; Waki, Michinori; Matsumoto, Aki; Lancelin, Jean Marc; Kohda, Daisuke; Tate, Shin‐ichi; Inagaki, Fuyuhiko; Fujii, Nobutaka

doi:10.1016/0167-4838(93)90183-r

Cited by 101 publications

(66 citation statements)

References 16 publications

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“…It was not possible to solvate the anionic detergent SDS in the presence of either wildtype tachyplesin I or TPY4 even in a low molar excess (2-fold). Earlier studies have also reported precipitation or turbid solutions when wild-type tachyplesin I was mixed with negatively charged lipids (5,7,38). Certainly, this indicates that ionic interactions may play an important role in the activity of tachyplesins.…”

Section: Discussionmentioning

confidence: 98%

“…A typical example is tachyplesin I (Figure 1a), a 17-residue cyclic peptide isolated from the hemocytes of the horseshoe crab, Tachyplesus tridentatus (2), which is active against fungi and Gram-positive and Gram-negative bacteria (3). In aqueous solution, tachyplesin I adopts a -hairpin fold stabilized by two disulfide bridges (4,5). Antimicrobial activity is greatly decreased when the four cysteine residues are alkylated or mutated to alanine (TPA4, 1 Figure 1a) (3,6,7), suggesting that the two disulfide bridges are necessary for activity.…”

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confidence: 99%

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Solution and Micelle-Bound Structures of Tachyplesin I and Its Active Aromatic Linear Derivatives^,

2002

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Tachyplesin I is a 17-residue peptide isolated from the horseshoe crab, Tachyplesus tridentatus. It has high antimicrobial activity and adopts a β-hairpin conformation in solution stabilized by two cross-strand disulfide bonds. We report an NMR structural investigation of wild-type tachyplesin I and three linear derivatives (denoted TPY4, TPF4, and TPA4 in which the bridging cysteine residues are uniformly replaced with tyrosine, phenylalanine, and alanine, respectively). The three-dimensional aqueous solution structures of the wild type and the active variant TPY4 reveal very similar β-hairpin conformations. In contrast, the inactive variant TPA4 is unstructured in solution. The arrangement of the tyrosine side chains in the TPY4 structure suggests that the β-hairpin is stabilized by aromatic ring stacking interactions. This is supported by experiments in which the β-hairpin structure of TPF4 is disrupted by the addition of phenol, but not by the addition of an equimolar amount of cyclohexanol. We have also determined the structures of wild-type tachyplesin I and TPY4 in the presence of dodecylphosphocholine micelles. Both peptides undergo significant conformational rearrangement upon micelle association. Analysis of the micelle-associated peptide structures shows an increased level of exposure of specific hydrophobic side chains and an increased hydrophobic integy moment. Comparison of the structures in micelle and aqueous solution for both wildtype tachyplesin I and TPY4 reveals two requirements for high antimicrobial activity: a β-hairpin fold in solution and the ability to rearrange critical side chain residues upon membrane association. ReceiVed May 23, 2002; ReVised Manuscript ReceiVed August 17, 2002 ABSTRACT: Tachyplesin I is a 17-residue peptide isolated from the horseshoe crab, Tachyplesus tridentatus. It has high antimicrobial activity and adopts a -hairpin conformation in solution stabilized by two crossstrand disulfide bonds. We report an NMR structural investigation of wild-type tachyplesin I and three linear derivatives (denoted TPY4, TPF4, and TPA4 in which the bridging cysteine residues are uniformly replaced with tyrosine, phenylalanine, and alanine, respectively). The three-dimensional aqueous solution structures of the wild type and the active variant TPY4 reveal very similar -hairpin conformations. In contrast, the inactive variant TPA4 is unstructured in solution. The arrangement of the tyrosine side chains in the TPY4 structure suggests that the -hairpin is stabilized by aromatic ring stacking interactions. This is supported by experiments in which the -hairpin structure of TPF4 is disrupted by the addition of phenol, but not by the addition of an equimolar amount of cyclohexanol. We have also determined the structures of wild-type tachyplesin I and TPY4 in the presence of dodecylphosphocholine micelles. Both peptides undergo significant conformational rearrangement upon micelle association. Analysis of the micelle-associated peptide structures shows an increased level of expo...

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Section: Discussionmentioning

confidence: 98%

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confidence: 99%

Solution and Micelle-Bound Structures of Tachyplesin I and Its Active Aromatic Linear Derivatives^,

2002

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“…Like most of the studies that have evaluated antiviral activity in aquatic invertebrates, the cell culture model is a heterologous model (Prescott et al 1966, Li & Traxler 1972, Azumi et al 1990, Tamamura et al 1993, Lee & Maruyama 1998. No homologous viral model is available for OsHV-1 because of the lack of an oyster cell line, and OsHV-1 replication has failed in insect, fish and mam- Although several molecules extracted from invertebrates have already been characterized with broad anti-microbial activity (Nakamura et al 1988, Mitta et al 2000, Zasloff 2002), antiviral effects have rarely been reported.…”

Section: Discussionmentioning

confidence: 99%

In vitro research of anti-HSV-1 activity in different extracts from Pacific oysters Crassostrea gigas

Olicard¹,

Didier²,

Marty³

et al. 2005

Dis. Aquat. Org.

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Mortalities related to the detection of Ostreid Herpesvirus 1 (OsHV-1) have been previously reported in France among larvae and spat of the Pacific oyster Crassostrea gigas. Adult oysters appear less sensitive to herpesvirus infections, although OsHV-1 has been detected in adults without signs of disease or mortality. This suggests that the virus is able to persist in its host and that adult oysters may be able to control OsHV-1 infection. Little is known about antiviral substances in invertebrates. The present work concerns the research of antiviral substances in adult oyster C. gigas, where putative antiviral activities were monitored using 3 strategies: (1) in metabolites with variable polarity, (2) in peptidic extracts and (3) in crude haemolymph. In vitro antiviral assays were based on inhibition of Herpes simplex virus type 1 (HSV-1) replication in Vero cell monolayers. All extracts presented no cytotoxicity. Antiviral activity was detected in the fresh filtered haemolymph (EC 50 :425 µg ml -1) and seasonal variation of the haemolymph antiviral activity was monitored.KEY WORDS: Oyster · Crassostrea gigas · Antiviral defence · OsHV-1 · HSV-1 · Antiviral peptides · Haemolymph Resale or republication not permitted without written consent of the publisherDis Aquat Org 67: [141][142][143][144][145][146][147] 2005 reported (Le Deuff et al. 1996). Adult oysters could be more resistant to viral infections in developing effective immunity against OsHV-1.Despite the impact that viral diseases have on shellfish cultures, little is known about how shellfish farmers can prevent and treat viral infections or about how shellfish control viral diseases. Although invertebrates do not produce specific antibodies (Shapiro 1975), they may rely on their innate defence for host protection against viruses. Reports on viruses infecting bivalves are available today, but those focusing on antiviral defence mechanisms are poorly documented. Antiviral substances have rarely been reported in bivalves and are particularly rare for Crassostrea gigas (Prescott et al. 1966, Li & Traxler 1972, Bachère et al. 1989, Lee & Maruyama 1998.The main objective of the present study was the detection of antiviral substances in adult Crassostrea gigas oysters. Antiviral and cytotoxicity activities of oyster aqueous and alcoholic extracts were evaluated in vitro against Herpes simplex virus type 1 (HSV-1) infecting Vero cells. Cytotoxicity activity assays were performed in order to demonstrate that oyster extracts were not causing Vero cell mortality. The protocol used in the present study to prepare aqueous and alcoholic oyster extracts was previously developed for extraction of marine bioactive substances (Hellio et al. 2000). Antiviral activity of oyster peptide extracts and crude haemolymph was also monitored. Peptide extraction from oyster tissues was developed on the basis of previous works on peptidic antimicrobial substances from frogs (Amiche et al. 2000, Matutte et al. 2000, lobsters (Nousiainen et al. 1998), and mussels (Mitta ...

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“…[179,180] One of the first inhibitors of CXCR4 described was the natural peptide polyphemusin II, [171,172] ]-polyphemusin II), [181] (Figure 29). T22 exhibits a wellstructured β-hairpin conformation by NMR, [182] and thus constituted a good starting point for PEM design. Several PEM libraries were synthesized and tested in iterative rounds of optimization.…”

Section: Pseudomycinsmentioning

confidence: 99%

Recent Progress in the Discovery of Macrocyclic Compounds as Potential Anti-Infective Therapeutics

Obrecht¹,

Robinson²,

Bernardini

et al. 2009

CMC

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O (2009Recent progress in the discovery of macrocyclic compounds as potential anti-infective therapeutics AbstractNovel therapeutic strategies are urgently needed for the treatment of serious diseases caused by viral, bacterial and parasitic infections, because currently used drugs are facing the problem of rapidly emerging resistance. There is also an urgent need for agents that act on novel pathogen-specific targets, in order to expand the repertoire of possible therapies. The high throughput screening of diverse small molecule compound libraries has provided only a limited number of new lead series, and the number of compounds acting on novel targets is even smaller. Natural product screening has traditionally been very successful in the anti-infective area. Several successful drugs on the market as well as other compounds in clinical development are derived from natural products. Amongst these, many are macrocyclic compounds in the 1-2 kDa size range. This review will describe recent advances and novel drug discovery approaches in the anti-infective area, focusing on synthetic and natural macrocyclic compounds for which in vivo proof of concept has been established. The review will also highlight the Protein Epitope Mimetics (PEM) technology as a novel tool in the drug discovery process. Here the structures of naturally occurring antimicrobial and antiviral peptides and proteins are used as starting points to generate novel macrocyclic mimetics, which can be produced and optimized efficiently by combinatorial synthetic methods. Several recent examples highlight the great potential of the PEM approach in the discovery of new anti-infective agents. Abstract:Novel therapeutic strategies are urgently needed for the treatment of serious

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A comparative study of the solution structures of tachyplesin I and a novel anti-HIV synthetic peptide, T22 ([Tyr5,12, Lys7]-polyphemusin II), determined by nuclear magnetic resonance

Cited by 101 publications

References 16 publications

Solution and Micelle-Bound Structures of Tachyplesin I and Its Active Aromatic Linear Derivatives^,

Solution and Micelle-Bound Structures of Tachyplesin I and Its Active Aromatic Linear Derivatives^,

In vitro research of anti-HSV-1 activity in different extracts from Pacific oysters Crassostrea gigas

Recent Progress in the Discovery of Macrocyclic Compounds as Potential Anti-Infective Therapeutics

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A comparative study of the solution structures of tachyplesin I and a novel anti-HIV synthetic peptide, T22 ([Tyr5,12, Lys7]-polyphemusin II), determined by nuclear magnetic resonance

Cited by 101 publications

References 16 publications

Solution and Micelle-Bound Structures of Tachyplesin I and Its Active Aromatic Linear Derivatives,

Solution and Micelle-Bound Structures of Tachyplesin I and Its Active Aromatic Linear Derivatives,

In vitro research of anti-HSV-1 activity in different extracts from Pacific oysters Crassostrea gigas

Recent Progress in the Discovery of Macrocyclic Compounds as Potential Anti-Infective Therapeutics

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Product

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Solution and Micelle-Bound Structures of Tachyplesin I and Its Active Aromatic Linear Derivatives^,

Solution and Micelle-Bound Structures of Tachyplesin I and Its Active Aromatic Linear Derivatives^,