ChemInform Abstract: The Design, Synthesis and Conformation of Some New β‐Hairpin Mimetics: Novel Reagents for Drug and Vaccine Discovery

Robinson, John A.

doi:10.1002/chin.200025280

Cited by 7 publications

(11 citation statements)

References 55 publications

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“…We used structure-based methods to discover low nM inhibitors of the Tat-TAR interaction in BIV (15,16). This was achieved by mimicking (14) the ␤-hairpin formed by the RNA-binding domain of BIV Tat protein upon binding its cognate TAR (12,13) with cyclic peptides stabilized by the heterochiral D-Pro-LPro template (17). Given the similarities in sequence and secondary structures between BIV and HIV Tat and TAR, we reasoned that the same family of constrained cyclic peptides may also be able to act as HIV Tat inhibitors.…”

Section: Resultsmentioning

confidence: 99%

Simultaneous recognition of HIV-1 TAR RNA bulge and loop sequences by cyclic peptide mimics of Tat protein

Davidson

Leeper

Athanassiou

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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165

226

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The interaction of the HIV-1 transactivator protein Tat with its transactivation response (TAR) RNA is an essential step in viral replication and therefore an attractive target for developing antivirals with new mechanisms of action. Numerous compounds that bind to the 3-nt bulge responsible for binding Tat have been identified in the past, but none of these molecules had sufficient potency to warrant pharmaceutical development. We have discovered conformationally-constrained cyclic peptide mimetics of Tat that are specific nM inhibitors of the Tat-TAR interaction by using a structure-based approach. The lead peptides are nearly as active as the antiviral drug nevirapine against a variety of clinical isolates in human lymphocytes. The NMR structure of a peptide-RNA complex reveals that these molecules interfere with the recruitment to TAR of both Tat and the essential cellular cofactor transcription elongation factor-b (P-TEFb) by binding simultaneously at the RNA bulge and apical loop, forming an unusually deep pocket. This structure illustrates additional principles in RNA recognition: RNA-binding molecules can achieve specificity by interacting simultaneously with multiple secondary structure elements and by inducing the formation of deep binding pockets in their targets. It also provides insight into the P-TEFb binding site and a rational basis for optimizing the promising antiviral activity observed for these cyclic peptides.NMR ͉ transcription elongation factor-b ͉ antiviral ͉ Tat-TAR interaction ͉ RNA recognition T ranscription of the HIV-1 RNA in infected cells is strongly activated by the complex between the viral Tat protein and its cognate transactivation response (TAR) RNA, a 59-nt RNA found at the 5Ј end of all nascent viral transcripts (Fig. 1A). Tat and its cellular cofactor, the transcription elongation factor-b (P-TEFb), are recruited to the elongating RNA polymerase II (RNAP II) through interactions with TAR and are required for reactivation of the integrated proviral genome in latently infected cells (1). The cooperative binding of Tat and P-TEFb to TAR activates the CDK9 kinase of P-TEFb that phosphorylates RNAP II and the repressive NELF factors, leading to greatly enhanced RNAP II processivity (1-3).The Tat-TAR complex is an attractive target for developing new antivirals because the interaction between Tat and TAR is unique to the virus, whereas P-TEFb is used widely for transcription of most host genes. Furthermore, TAR is extremely conserved among viral isolates and P-TEFb plays a key role in promoting infectivity through the Tat-TAR complex and in the emergence from latency. These considerations have led to the synthesis and evaluation of numerous small-molecule and peptidic inhibitors of the Tat-TAR interaction during the last 15 years (4-7). However, none of these molecules had sufficient potency or selectivity to progress into preclinical studies and, indeed, inhibiting the Tat-TAR interaction has proven challenging. First, there is little precedent for the pharmacological disruption...

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Section: Resultsmentioning

confidence: 99%

Simultaneous recognition of HIV-1 TAR RNA bulge and loop sequences by cyclic peptide mimics of Tat protein

Davidson

Leeper

Athanassiou

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

165

226

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“…CD spectra were measured on a JASCO J-810 spectropolarimeter from 190 to 400 nm using a 0.2-cm-path-length cell. Scans (3)(4)(5) were accumulated at ambient temperature with a scanning speed of 100 nm min −1 , using 0.56 mM methanol solutions for peptides 3 and 4 at 298 K. For peptidomimetic 5 a 0.25-mM methanol solution was analysed at 273-323 K, and for 6 a 0.5-mM methanol solution was analysed at 273-323 K.…”

Section: Spectroscopymentioning

confidence: 99%

“…Proteins are composed of a few regular structural elements, foremost α-helices, β-sheets and turns [1]. These building blocks are also involved in molecular recognition and are therefore potential candidates for drug design [2,3]. Compared with α-helices, β-hairpins have been studied less frequently [4][5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Interplaying factors for the formation of photoswitchable β‐hairpins: the advantage of a flexible switch

Varedian

Erdélyi

Persson

et al. 2008

Journal of Peptide Science

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A series of peptidomimetics intended to promote the beta-hairpin motif have been studied. Structural variations include a turn region with and without a photoswitchable chromophore, and strands with amino acid side chains supporting various degrees of interstrand interactions for hairpin stabilisation. The propensity of the compounds to form beta-hairpins was evaluated experimentally by NMR spectroscopy, translational self-diffusion studies and CD spectroscopy. In the presence of hairpin stabilising interstrand interactions, the structurally flexible stilbene chromophore appeared to be well compatible with the imposed secondary structure.

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“…These scaffolds are inspired by the D-Pro-L-Pro dipeptide 78 (Figure 8), known to adopt a stable type II'-β turn [181] and designed to provide two reactive handles which can be used to attach N-and C-terminal polypeptide chains. Among them, the diketopiperazine incorporating a substituted proline 79 (Figure 8) has demonstrated to be a useful scaffold [182]. On the other hand, diverse biaryl scaffolds have been (Figure 8) [187].…”

Section: Local Rigidification Using Dipeptide Mimeticsmentioning

confidence: 99%

“…Diverse β-turn mimetics have been used as constraining scaffolds in β-hairpin turn peptidomimetics [235] including dibenzofurans (80 in Figure 8) [185]; substituted diphenylacetylene (81 in Figure 8) [186]; diureas (86 in Figure 8) [189] or diketopiperazines incorporating substituted proline derivatives (79 in Figure 8) [182] using or not β-strand enhancers.…”

Section: Designing Peptides and Peptidomimetics With Preferred Conformentioning

confidence: 99%

Designing Peptidomimetics

Pérez¹

2018

CTMC

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The concept of a peptidomimetic was coined about forty years ago. Since then, enormous effort and interest have been devoted to mimic the properties of peptides with small molecules or pseudopeptides. The present report aims to review different approaches described in the past to succeed in this goal. Basically, there are two different approaches to design peptidomimetics: a medicinal chemistry approach, where parts of the peptide are successively replaced by non-peptide moieties until getting a non-peptide molecule and a biophysical approach, where a hypothesis of the bioactive form of the peptide is sketched and peptidomimetics are designed based on hanging the appropriate chemical moieties on diverse scaffolds. Although both approaches have been used in the past, the former has been more widely used to design peptidomimetics of secretory peptides, whereas the latter is nowadays getting momentum with the recent interest in designing protein-protein interaction inhibitors. The present report summarizes the relevance of the information gathered from structure-activity studies, together with a short review of the strategies used to design new peptide analogs and surrogates. In the following section, there is a short discussion on the characterization of the bioactive conformation of a peptide, to continue describing the process of designing conformationally constrained analogs producing first and second generation peptidomimetics. Finally, there is a section devoted to reviewing the use of organic scaffolds to design peptidomimetics based on the information available on the bioactive conformation of the peptide.

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ChemInform Abstract: The Design, Synthesis and Conformation of Some New β‐Hairpin Mimetics: Novel Reagents for Drug and Vaccine Discovery

Cited by 7 publications

References 55 publications

Simultaneous recognition of HIV-1 TAR RNA bulge and loop sequences by cyclic peptide mimics of Tat protein

Simultaneous recognition of HIV-1 TAR RNA bulge and loop sequences by cyclic peptide mimics of Tat protein

Interplaying factors for the formation of photoswitchable β‐hairpins: the advantage of a flexible switch

Designing Peptidomimetics

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