Rational conversion of noncontinuous active region in proteins into a small orally bioavailable macrocyclic drug-like molecule: The HIV-1 CD4:gp120 paradigm

Hurevich, Mattan; Swed, Avi; Joubran, Salim; Cohen, Shira; Freeman, Noam S.; Britan-Rosich, Elena; Briant-Longuet, Laurence; Bardy, Martine; Devaux, Christian; Kotler, Moshe; Hoffman, Amnon; Gilon, Chaim

doi:10.1016/j.bmc.2010.04.053

Cited by 11 publications

(11 citation statements)

References 24 publications

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“…Analyzing the SAR of the endogenous peptide ligand, endomorphin-2 (Tyr-Pro-Phe-Phe-NH 2 ), we noticed that the spacer amino acid between Tyr and Phe, proline, is naturally N-alkylated. Therefore, to keep both the integrity of the pharmacophores and still enable the cyclization, we decided to alkylate the α-nitrogen of the TAPS D-Arginine with various epsilon-amino alkyl chains and use it as the second anchor for cyclization (Gazal et al, 2001;Hurevich et al, 2010).…”

Section: Design Of the Backbone Taps C(n-m) Focused Librarymentioning

confidence: 99%

“…Establishing a simple and straightforward synthesis of orthogonally protected glycine building units (abbreviated Gly-BU) was an essential step for the facile preparation of backbonecyclic peptides (Hurevich et al, 2010(Hurevich et al, , 2013. However, using a Gly-BU to replace a non-glycine amino acid from the parent peptide may decrease the potency and selectivity of the resulting backbone-cyclic peptides ( Figure 1C).…”

Section: Introductionmentioning

confidence: 99%

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Cyclizing Painkillers: Development of Backbone-Cyclic TAPS Analogs

Talhami

Swed

Hess³

et al. 2020

Front. Chem.

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Painkillers are commonly used medications. Native peptide painkillers suffer from various pharmacological disadvantages, while small molecule painkillers like morphine are highly addictive. We present a general approach aimed to use backbone-cyclization to develop a peptidomimetic painkiller. Backbone-cyclization was applied to transform the linear peptide Tyr-Arg-Phe-Sar (TAPS) into an active backbone-cyclic peptide with improved drug properties. We designed and synthesized a focused backbone-cyclic TAPS library with conformational diversity, in which the members of the library have the generic name TAPS c(n-m) where n and m represent the lengths of the alkyl chains on the nitrogens of Gly and Arg, respectively. We used a combined screening approach to evaluate the pharmacological properties and the potency of the TAPS c(n-m) library. We focused on an in vivo active compound, TAPS c(2-6) , which is metabolically stable and has the potential to become a peripheral painkiller being a full μ opioid receptor functional agonist. To prepare a large quantity of TAPS c(2-6) , we optimized the conditions of the on-resin reductive alkylation step to increase the efficiency of its SPPS. NMR was used to determine the solution conformation of the peptide lead TAPS c(2-6) .

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Section: Design Of the Backbone Taps C(n-m) Focused Librarymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cyclizing Painkillers: Development of Backbone-Cyclic TAPS Analogs

Talhami

Swed

Hess³

et al. 2020

Front. Chem.

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“…The authors demonstrated that this method is feasible by preparing a small inhibitor of human immunodeficiency virus (HIV) infection. The lead compound, CG-1, proved orally available in a rat model [66] (Fig. 8).…”

Section: 2 Cycloscan: Development Of Backbone Cyclic Peptides and mentioning

confidence: 99%

“…Structure of the backbone cyclic peptide analog of the CD4 non-contiguous active region, CG-1, [66]. …”

Section: Figurementioning

confidence: 99%

Conversion of Protein Active Regions into Peptidomimetic Therapeutic Leads Using Backbone Cyclization and Cycloscan – How to Do it Yourself!

Rubin

Tal‐Gan

Gilon

et al. 2018

CTMC

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Protein-protein Interactions (PPIs) are particularly important for controlling both physiologic and pathologic biological processes but are difficult to target due to their large and/or shallow interaction surfaces unsuitable for small molecules. Linear peptides found in nature interact with some PPIs, and protein active regions can be used to design synthetic peptide compounds for inhibition of PPIs. However, linear peptides are limited therapeutically by poor metabolic and conformational stability, which can compromise their bioactivity and half-life. Cyclic peptidomimetics (modified peptides) can be used to overcome these challenges because they are more resistant to metabolic degradation and can be engineered to adopt desired conformations. Backbone cyclization is a strategy that we developed to improve drug-like properties of linear peptide leads without jeopardizing the integrity of functionally relevant side-chains. Here, we provide the first description of an entire approach for developing backbone cyclized peptide compounds, based upon two straightforward 'ABC' and 'DEF' processes. We present practical examples throughout our discussion of revealing active regions important for PPIs and identifying critical pharmacophores, as well as developing backbone cyclized peptide libraries and screening them using cycloscan. Finally, we review the impact of these advances and provide a summary of current ongoing work in the field.

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“…Its particular structure promotes the formation of hydrophobic and hydrogen bond interactions with specific residues in the Phe 43 cavity; therefore interfering in gp120-CD4 protein-protein interactions. Another example comes from Gilon and co-workers that developed a novel method to convert the non-continuous active regions in CD4 into small macrocyclic molecules with anti-HIV-1 activity [107]. Compound 21 was shown to inhibit HIV-1 infection in the low-micromolar range in vitro and had excellent oral bioavailability and good metabolic stability ( Figure 11).…”

Section: Targeting Cd4 Binding Site On Gp120mentioning

confidence: 99%

Entry Inhibitors Directed Towards Glycoprotein gp120: An Overview on a Promising Target for HIV-1 Therapy

Flores

Quesada²

2013

CMC

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In spite of the unquestionable positive impact of HAART in the treatment of HIV infection, the discovery and development of novel agents directed towards other targets of the replicative cycle of the virus that differ from those targeted by the clinically approved drugs, emerges nowadays as an imperative need. The blockade of HIV entry is a highly promising strategy against the pathogen and glycoprotein gp120 is a central actor in this process. This review discusses the current status in the research of anti-HIV agents targeting specifically the envelope protein gp120. The diverse approaches devoted to the achievement of therapeutic agents against gp120 currently under study are organized and analyzed critically according to their specific mechanism of inhibition and structural features.2

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Rational conversion of noncontinuous active region in proteins into a small orally bioavailable macrocyclic drug-like molecule: The HIV-1 CD4:gp120 paradigm

Cited by 11 publications

References 24 publications

Cyclizing Painkillers: Development of Backbone-Cyclic TAPS Analogs

Cyclizing Painkillers: Development of Backbone-Cyclic TAPS Analogs

Conversion of Protein Active Regions into Peptidomimetic Therapeutic Leads Using Backbone Cyclization and Cycloscan – How to Do it Yourself!

Entry Inhibitors Directed Towards Glycoprotein gp120: An Overview on a Promising Target for HIV-1 Therapy

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