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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Since the mid-2000s, progress has been made with the development of small-molecule mimics of Smac. One example published in 2013 describes the synthesis and testing of peptidomimetics, whose structure is based on the AVPI tetrapeptide IAP-binding motif present in the N-terminus of mature Smac. These peptidomimetic compounds can bind to the protein Livin with high affinity; however, none was progressed to the clinical stage.
The Application of Fragment-based Approaches to the Discovery of Drugs for Neglected Tropical Diseases
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Christina Spry, Anthony G. Coyne
The NS2B-NS3 protease complex is one of the best-studied targets for the development of drugs against the DENV (Behnam et al. 2016). This complex catalyzes the post-translational cleavage of the DENV polyprotein and is essential for viral replication; the proteolytic activity is localized to the N-terminus of NS3, while NS2B contributes to substrate recognition (Nitsche et al. 2014). A number of inhibitors of the DENV protease have been identified and these can be broadly classified into (i) peptidic and peptidomimetic inhibitors and (ii) non-peptidic small molecule inhibitors (reviewed by Nitsche et al. (2014)).
Lung transporters and absorption mechanisms in the lungs
Published in Anthony J. Hickey, Heidi M. Mansour, Inhalation Aerosols, 2019
Mohammed Ali Selo, Hassan H.A. Al-Alak, Carsten Ehrhardt
The oligopeptide transporters PEPT1 and PEPT2 are proton-coupled transporters belonging to the SLC15 subfamily (96,97). PEPTs can transport a wide range of substrates ranging from di- and tri-peptides to peptidomimetic drugs, such as angiotensin-converting enzyme inhibitors, β-lactam antibiotics, antivirals, anti-neoplastics, and delta-aminolevulinic acid (98–101).
Strategies for targeting undruggable targets
Published in Expert Opinion on Drug Discovery, 2022
Gong Zhang, Juan Zhang, Yuting Gao, Yangfeng Li, Yizhou Li
Peptide motif participates naturally in PPI. However, the truncated linear peptide does not necessarily fold correctly, losing conformational stability and bioactivity. Therefore, a panel of strategies to stabilize peptide conformation and reduce proteolysis susceptibility have been developed. For α-helix motifs, the staple peptide is an efficient therapeutic entity to facilitate the folding of secondary structures[32]. The cyclic peptide is another classical form of entity, especially for stretched or coiled peptides without well-defined secondary structures[33]. Altogether, the linear/cyclic/staple modes represent diverse peptide conformations adopted to deal with undruggable targets (Figure 1c). Peptidomimetics/proteomimetics represent another category of peptide-derived drugs generated by rational design, display technologies, or library screening. They may contain unnatural amino acid building blocks and cyclic structures, providing advantages over native peptides in aspects of pharmacological property and chemical diversity. Peptidomimetics have been developed to target suppressor of cytokine signaling (SOSC) in the treatment of atherosclerosis and inflammation [34,35].
Antimicrobial peptides and other peptide-like therapeutics as promising candidates to combat SARS-CoV-2
Published in Expert Review of Anti-infective Therapy, 2021
Masoumeh Sadat Mousavi Maleki, Mosayeb Rostamian, Hamid Madanchi
Peptidomimetics are designed based on small protein-like chains or small molecules that mimic the behavior of a peptide and have regulated molecular properties, such as high stability or biological activity. The use of peptidomimetics is a very powerful strategy for designing small molecule-based drugs as enzyme inhibitors or receptor ligands [106]. These compounds mimic a natural peptide or a protein of the viruses and have the ability to interact with their biological targets and produce the same biological effects [107]. There are different types of changes to create peptidomimetics with improved drug properties, including local changes, such as the binding of nonstandard amino acids, and general changes, such as forming a circular end in polypeptide chains during a cyclization process. Cyclization is one of the most common strategies used to convert peptides into drugs and pharmacologically active agents [108].
Coronaviruses
Published in Expert Opinion on Therapeutic Patents, 2021
Capasso et al. [28] discuss the three pairs of cysteine proteases present in the three CoVs that provoked outbreaks, SARS, MERS and SARS-CoV-2, with a particular stress on the last one (but, as already mentioned, there is a relevant homology between the ortholog proteins from these three viruses). The 3D crystal structures of both SARS-CoV-2 proteases (MPro and PLP) are available, alone and in complex with many inhibitors. In fact, this allowed for interesting structure-based drug design campaigns of protease inhibitors (PIs) targeting all these proteins, as discussed in detail in the article [28]. Most such compounds are peptidomimetics incorporating Michael acceptors of the aldehyde, thioketone, α-ketoamides, trans-α,β-unsaturated alkyl/benzyl esters, chloromethyl ketones, hydroxymethyl ketones type or are disulfides/dithiocarbamtes which react with the catalytic triad cysteine present within the enzyme active site [28]. However, non-peptidomimetic inhibitors were also reported, such as disulfiram and other disulfides incorporating various heterocyclic and aromatic scaffolds, fused 1,2,3-triazoles, ebselen, tideglusib and natural products (flavonoids, carmofur, shikonin, etc.). In the case of the two SARS-CoV-2 proteases, many low nanomolar inhibitors were already detected, some of which were also highly effective in inhibiting the viral replication in vivo, making this class of compounds among the most interesting ones in the development of novel antivirals.