Peptides and Peptide Mimics as Modulators of Apoptotic Pathways

Orzáez, Mar; Gortat, Anna; Mondragón, Laura; Pérez‐Payá, Enrique

doi:10.1002/cmdc.200800246

Cited by 7 publications

(3 citation statements)

References 195 publications

(185 reference statements)

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“…In order to design drugs with BH3 functionality, peptide analogs and surrogates are expected to be more resistant to proteolytic enzymes and can also be designed to exhibit higher populations of the bioactive conformation in solution compared to the original linear peptides. Diverse strategies have been used for the discovery of potent peptide surrogates of the BH3 domain ( Orzáez et al, 2009 ). As a general strategy, increased resistance to proteolytic enzymes can be carried out by replacing peptide bonds by isosteres or using a holistic approach, constructing retro-inverso analogs or peptoids ( Perez et al, 2002 ; Akram et al, 2014 ; Perez, 2018 ).…”

Section: The Bh3-bcl-2 Interactionmentioning

confidence: 99%

Computational Modeling as a Tool to Investigate PPI: From Drug Design to Tissue Engineering

Pérez

2021

Front. Mol. Biosci.

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Protein-protein interactions (PPIs) mediate a large number of important regulatory pathways. Their modulation represents an important strategy for discovering novel therapeutic agents. However, the features of PPI binding surfaces make the use of structure-based drug discovery methods very challenging. Among the diverse approaches used in the literature to tackle the problem, linear peptides have demonstrated to be a suitable methodology to discover PPI disruptors. Unfortunately, the poor pharmacokinetic properties of linear peptides prevent their direct use as drugs. However, they can be used as models to design enzyme resistant analogs including, cyclic peptides, peptide surrogates or peptidomimetics. Small molecules have a narrower set of targets they can bind to, but the screening technology based on virtual docking is robust and well tested, adding to the computational tools used to disrupt PPI. We review computational approaches used to understand and modulate PPI and highlight applications in a few case studies involved in physiological processes such as cell growth, apoptosis and intercellular communication.

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Section: The Bh3-bcl-2 Interactionmentioning

confidence: 99%

Computational Modeling as a Tool to Investigate PPI: From Drug Design to Tissue Engineering

Pérez

2021

Front. Mol. Biosci.

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“…For example, in TB, the induction of apoptosis might be therapeutic, not only through the deregulation of the expression of In summary, the Mtb's protein-and lipid-based molecules significantly affect apoptosis. Therefore, various efforts to activate or inhibit apoptosis have been implemented as therapeutic strategies to fight Mtb infections [90,91]. For example, in TB, the induction of apoptosis might be therapeutic, not only through the deregulation of the expression of virulence factors that inhibit the process but also through the direct activation of components, such as initiator or effector caspases, similar to other pathologies or health conditions [92].…”

Section: Modulation Of Apoptosis In the Mtb Infection: Lipid Molecule...mentioning

confidence: 99%

Virulence Factors of Mycobacterium tuberculosis as Modulators of Cell Death Mechanisms

et al. 2023

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Mycobacterium tuberculosis (Mtb) modulates diverse cell death pathways to escape the host immune responses and favor its dissemination, a complex process of interest in pathogenesis-related studies. The main virulence factors of Mtb that alter cell death pathways are classified according to their origin as either non-protein (for instance, lipomannan) or protein (such as the PE family and ESX secretion system). The 38 kDa lipoprotein, ESAT-6 (early antigen-secreted protein 6 kDa), and another secreted protein, tuberculosis necrotizing toxin (TNT), induces necroptosis, thereby allowing mycobacteria to survive inside the cell. The inhibition of pyroptosis by blocking inflammasome activation by Zmp1 and PknF is another pathway that aids the intracellular replication of Mtb. Autophagy inhibition is another mechanism that allows Mtb to escape the immune response. The enhanced intracellular survival (Eis) protein, other proteins, such as ESX-1, SecA2, SapM, PE6, and certain microRNAs, also facilitate Mtb host immune escape process. In summary, Mtb affects the microenvironment of cell death to avoid an effective immune response and facilitate its spread. A thorough study of these pathways would help identify therapeutic targets to prevent the survival of mycobacteria in the host.

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“…Controlling apoptotic pathways with peptides is showing increasing promise as a strategy in drug development. Peptides are essential tools for drug discovery, as well as preclinical and pharmaceutical drug development [80].…”

Section: New Peptides Drug Discoverymentioning

confidence: 99%

Protein Based Drug Discovery

Joshi¹,

Boraste²,

Khairnar³

et al. 2009

Int J of Drug Disc

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Abstract-New drug target discovery is currently very popular with a great potential for advancing biomedical research and chemical genomics. Drug discovery is the process of discovering and designing drugs that includes target identification, target validation, lead identification, lead optimization and introduction of the new drugs to the public. G protein-coupled receptors are one of the most important drug targets. In the current scenario of drug research, approximately 60% of drug target molecules are located at the cell surface, and half of them are GPCRs. Fragment-based drug discovery is established as an alternative approach to high-throughput screening for generating novel small molecule drug candidates. Nanotechnology-based drug delivery systems have seen recent popularity due to their favorable physical, chemical, and biological properties, and great efforts have been made to target nanoDDSs to specific cellular receptors. Protein-protein interactions regulate a wide variety of important cellular pathways, and therefore represent a highly populated class of targets for drug discovery. An analysis of individual proteinprotein interaction systems has recently yielded success in the discovery of drug-like inhibitors.

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Peptides and Peptide Mimics as Modulators of Apoptotic Pathways

Cited by 7 publications

References 195 publications

Computational Modeling as a Tool to Investigate PPI: From Drug Design to Tissue Engineering

Computational Modeling as a Tool to Investigate PPI: From Drug Design to Tissue Engineering

Virulence Factors of Mycobacterium tuberculosis as Modulators of Cell Death Mechanisms

Protein Based Drug Discovery

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