A Readily Applicable Strategy to Convert Peptides to Peptoid-based Therapeutics

Park, Minyoung; Wetzler, Modi; Jardetzky, Theodore S.; Barron, Annelise E.

doi:10.1371/journal.pone.0058874

Cited by 18 publications

(19 citation statements)

References 42 publications

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“…These unique features of peptoids may aid in revealing salient features of protein–protein interactions. 32 For example, the X-ray crystallographic structure of a peptomeric analogue of SFTI-1 containing N Lys in the P1 subsite revealed an interesting mechanism of proteolytic resistance. 39 The peptomer also provided insights into the mechanism of action of the serine protease family.…”

Section: Discussionmentioning

confidence: 99%

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Collagenolytic Matrix Metalloproteinase Activities toward Peptomeric Triple-Helical Substrates

2015

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Although collagenolytic matrix metalloproteinases (MMPs) possess common domain organizations, there are subtle differences in their processing of collagenous triplehelical substrates. In this study, we have incorporated peptoid residues into collagen model triple-helical peptides and examined MMP activities toward these peptomeric chimeras. Several different peptoid residues were incorporated into triplehelical substrates at subsites P3, P1, P1′, and P10′ individually or in combination, and the effects of the peptoid residues were evaluated on the activities of full-length MMP-1, MMP-8, MMP-13, and MMP-14/MT1-MMP. Most peptomers showed little discrimination between MMPs. However, a peptomer containing N-methyl Gly (sarcosine) in the P1′ subsite and N-isobutyl Gly (NLeu) in the P10′ subsite was hydrolyzed efficiently only by MMP-13 [nomenclature relative to the α1(I)772–786 sequence]. Cleavage site analysis showed hydrolysis at the Gly-Gln bond, indicating a shifted binding of the triple helix compared to the parent sequence. Favorable hydrolysis by MMP-13 was not due to sequence specificity or instability of the substrate triple helix but rather was based on the specific interactions of the P7′ peptoid residue with the MMP-13 hemopexin-like domain. A fluorescence resonance energy transfer triple-helical peptomer was constructed and found to be readily processed by MMP-13, not cleaved by MMP-1 and MMP-8, and weakly hydrolyzed by MT1-MMP. The influence of the triple-helical structure containing peptoid residues on the interaction between MMP subsites and individual substrate residues may provide additional information about the mechanism of collagenolysis, the understanding of collagen specificity, and the design of selective MMP probes.

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Section: Discussionmentioning

confidence: 99%

“…31 Systematic substitution of natural amino acids using peptoid residues can be considered as “peptoid scanning” that in principle is similar to the Ala scan commonly employed and provides valuable structural insight into protein–protein interactions. 32 …”

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confidence: 99%

Collagenolytic Matrix Metalloproteinase Activities toward Peptomeric Triple-Helical Substrates

2015

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“…A3G bound nine Vif-derived peptides from three distinct regions in Vif: residues 8-45 from the NTD, residues 154-192 from the CTD containing the conserved motif 161 PPLP 164 and a central region between residues 83-99 [230,231]. The A3G-derived peptides A3G [143][144][145][146][147][148][149][150][151][152][153][154][155][156][157] , A3G and A3G [263][264][265][266][267][268][269][270][271][272][273][274][275][276][277] bound fulllength Vif and Vif-CTD. The peptide array experiment revealed that peptides A3G 31-52 , A3G [166][167][168][169][170][171][172][173][174][175][176][177][178][179][180] , A3G 211-...…”

Section: (C) the Tat-p53 Interactionmentioning

confidence: 99%

“…The peptide, Fuzeon ® (Enfuvirtide) was approved for clinical use against HIV [84][85][86]268,269]. Current research in anti-HIV drug design is focused on stabilizing lead peptides using different strategies such as cyclization, peptoids and more [268][269][270][271][272][273].…”

Section: Conclusion and Future Perspectivementioning

confidence: 99%

Interactions of HIV-1 Proteins as Targets for Developing Anti-HIV-1 Peptides

2015

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Protein-protein interactions (PPI) are essential in every step of the HIV replication cycle. Mapping the interactions between viral and host proteins is a fundamental target for the design and development of new therapeutics. In this review, we focus on rational development of anti-HIV-1 peptides based on mapping viral-host and viral-viral protein interactions all across the HIV-1 replication cycle. We also discuss the mechanism of action, specificity and stability of these peptides, which are designed to inhibit PPI. Some of these peptides are excellent tools to study the mechanisms of PPI in HIV-1 replication cycle and for the development of anti-HIV-1 drug leads that modulate PPI.

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“…More recently, the modulation of peptoid helicity using the sergeant-and-solider effect was demonstrated [ 34 ]. The established solid phase peptoid synthesis method [ 35 ] and efficient post-synthetic modifications [ 36 , 37 , 38 , 39 , 40 , 41 ] afforded peptoids with greater structural diversity, thereby leading to their application in various functional entities including bioactive agents [ 42 , 43 , 44 , 45 , 46 , 47 ], biomimetic materials [ 48 , 49 , 50 , 51 ], sensors [ 52 , 53 ], and metal-chelating ligands [ 48 , 54 , 55 , 56 , 57 , 58 , 59 ].…”

Section: Introductionmentioning

confidence: 99%

Metalloporphyrin Dimers Bridged by a Peptoid Helix: Host-Guest Interaction and Chiral Recognition

2018

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Co-facial porphyrins have been designed to construct porphyrin tweezers with versatile molecular recognition capabilities. In this study, we synthesized metalloporphyrin–peptoid conjugates (MPPCs) displaying two metalloporphyrins on a peptoid scaffold with either achiral unfolded (1) or helical (2 and 3) secondary structures. Host–guest complexation of MPPCs was realized with various guests of different lengths and basicities, and the extent of complexation was measured by UV-vis and circular dichroism (CD) spectroscopic titration. Intermolecular and intramolecular chirality induction were observed on achiral and chiral peptoid backbones, respectively. Spectroscopic data indicated that a broad scope of achiral guests can be recognized by chiral 2; in particular, longer and more flexible guests were seen to bind more tightly on 2. In addition, chiral 2 provided a distinct CD couplet with dl-, d-, or l-Lys-OMe, which was a result of the diastereomeric host–guest complex formation. Our results indicated that MPPCs can recognize, contrast, and analyze various achiral, chiral, or racemic molecules. Based on co-facial metalloporphyrins present on peptoid scaffolds, we developed a novel class of porphyrin tweezers, which can be further utilized in asymmetric catalysis, molecular sensing, and drug delivery.

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A Readily Applicable Strategy to Convert Peptides to Peptoid-based Therapeutics

Cited by 18 publications

References 42 publications

Collagenolytic Matrix Metalloproteinase Activities toward Peptomeric Triple-Helical Substrates

Collagenolytic Matrix Metalloproteinase Activities toward Peptomeric Triple-Helical Substrates

Interactions of HIV-1 Proteins as Targets for Developing Anti-HIV-1 Peptides

Metalloporphyrin Dimers Bridged by a Peptoid Helix: Host-Guest Interaction and Chiral Recognition

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