Current Medicinal Chemistry (v.24, #20)

Multicyclic Peptides as Scaffolds for the Development of Tumor Targeting Agents by Anastasia Loktev, Uwe Haberkorn, Walter Mier (2141-2155).
The lack of specificity of traditional cytotoxic drugs triggers the development of anticancer agents with high selectivity to tumor-specific proteins. The unveiling of target structures such as EGFR or Her2 allows the focused development of novel therapies and has strongly advanced tumor treatment. Tumor-specific high-affinity ligands can be identified by using display techniques such as phage, yeast surface, ribosome and mRNA display. These techniques enable the screening of huge libraries, consequently providing a valuable alternative to rational drug development. In recent years, miniproteins and multicyclic peptides have become the preferred ligands expressed by these libraries. Due to their favorable pharmacokinetics and the ease of their synthesis, peptidic ligands overcome disadvantages of antibody derived therapeutics. Peptides that are structurally defined by a rigid scaffold are ideally suited for the use in display techniques. These molecules feature high stability and excellent affinities while offering the opportunity to randomize partial sequences to be used as binding sites. Structurization of the peptide scaffold can be achieved by different approaches, of which cyclization is one of the most commonly used. The favored cyclization strategies are based on amide or disulfide bridging and the use of synthetic braces or chemical linkers. The use of multicyclic peptides allows the simultaneous presentation of several different binding loops. Semisynthetic approaches enable the introduction of unnatural amino acids, increasing the diversity of the resulting peptide libraries. Given that, miniprotein scaffolds offer a wide range of potential applications and facilitate efficient screening of novel high-affinity ligands to be used in precise diagnosis and highly efficient cancer therapy.

Expression and Single Nucleotide Polymorphism of Poly (ADPRibose) Polymerase-1 in Gastrointestinal Tumours: Clinical Involvement by Sandra M. Martín-Guerrero, Josefa León, Rosa Quiles-Perez, Laura Belmonte, David Martin-Oliva, Ángeles Ruiz-Extremera, Javier Salmerón, José Antonio Muñoz-Gámez (2156-2173).
Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme that plays a critical role in diverse cellular functions, such as DNA damage detection and repair, transcriptional regulation and cell death. Furthermore, PARP-1 has emerged as a key player in the pathogenesis of multiple inflammatory diseases and has become a promising target for the treatment of cardiovascular disorders, neurodegenerative diseases and cancer. An increasing body of evidence has linked alterations in the expression levels of PARP-1, enzymatic activity and presence of polymorphism to gastrointestinal malignancies, including oesophageal, gastric, pancreas, liver and colorectal cancers. PARP inhibition has been proposed as a valuable strategy for treating these gastrointestinal disorders. This paper summarises the most significant current literature on the involvement of PARP-1 in gastrointestinal cancer, focusing in particular on its role in the development and occurrence of tumours, providing information about clinical trials and exploring therapeutic possibilities.

The Extracellular Bacterial HtrA Proteins as Potential Therapeutic Targets and Vaccine Candidates by Joanna Skórko-Glonek, Donata Figaj, Urszula Zarzecka, Tomasz Przepiora, Joanna Renke, Barbara Lipinska (2174-2204).
Background: An increasing resistance of bacteria to the commonly used antimicrobials forces to search for alternative or supportive ways to cure infections. Targeting virulence factors is one of such approaches. The bacterial HtrA proteins are strongly involved in virulence and the lack of functional HtrA in many cases impairs invasiveness of pathogens. HtrAs act by protecting the cells under stressful conditions as well as they take direct part in invasion of the host. The latter function is played predominantly by the recently identified extracellular fraction of HtrA. This review aims to evaluate HtrAs as therapeutic targets, including design of chemical inhibitors and vaccines. <P></P> Methods: We undertook a thorough search of bibliographic databases for peer-reviewed scientific literature. <P></P> Results: One hundred and sixty-four papers were included in the review. First, we briefly summarized key structural and functional properties of known HtrA proteins with the special focus on the extracellular HtrA fraction. Then we provided an overview of efforts and advancements to target HtrAs of pathogenic bacteria as a promising antimicrobial therapy. In some cases, encouraging results were obtained and application of HtrAspecific inhibitors protected tissues from damage and killed bacteria. Also promising reports concerning the use of HtrA as a protective antigen in several disease models have recently been published. <P></P> Conclusion: The findings of this review suggest that the exported HtrA proteins are very attractive therapeutic targets due to their accessibility, significance in virulence and immunogenicity. However, further extensive studies are still needed to develop a safe antimicrobial treatment.

Advances in Chemistry and Pharmacology of Triterpenoid Synthetic Dimers by Barbara Bednarczyk-Cwynar, Andrzej Günther (2205-2240).
This review focuses on advances in chemistry and pharmacology of synthetic triterpenoid dimers, obtained from natural compounds. Synthetic triterpenoid dimers are divided into specific subgroups based on the structure of main triterpenoid monomeric skeleton. Synthetic triterpenoid derivatives of dimeric structure can be obtained through the covalent linkage of the C-3 hydroxyl or another group, via the C-2 atom or the C-17 carboxyl group (mainly anhydrides, amides or esters). Some triterpenes can undergo chemical transformations leading to the formation of cyclic dimers or other types of dimers. Most of the obtained triterpenoid dimers have been subjected to pharmacological tests evaluating their biological activity, mainly antiviral (HIV-1 RT, HCVpp, VSVpp, HIV-RT-C8166-CCR5), cytotoxic (against e.g. 388, MCF-7, SF-268, NCIH460, KM20L2, DU-145, Hep-G2, A549, BGC-823, PC-3), anti-inflammatory (iNOS, RAW 264.7) and antidiabetic (RMGPa inhibition). The authors also reported the ability of some of the obtained cyclic triterpenoid dimers to recognize anions and to form self-assembled structures.

Hydroxychloroquine (HCQ) is known as one of the most fascinating synthetic antimalarial drugs during the last 50 years. It is currently among the most commonly employed medicines for the clinical treatment of rheumatic diseases, especially systemic lupus erythematosus and rheumatoid arthritis. In related mechanism studies, it has been found that HCQ possesses various immunomodulatory and anti-inflammatory activities. In addition, the effects of HCQ on anti-platelet, metabolic pathways, and antineoplasticity have also been disclosed in more recent studies. These significant findings on HCQ suggest the potential therapeutic applications of HCQ for treatment of many diseases, such as cancers, skin disease, antiphospholipid syndrome, etc. This review focuses on recent in vitro and clinical trials on its pharmacological mechanisms, therapeutic activities, and potential adverse effects.