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New drug candidates for cystic fibrosis

admin — Sun, 06 Nov 2011 22:12:14 +0000

Cystic Fibrosis (CF) affects about 30,000 people in the United States and approximately 70,000 people worldwide. Since the identification of the Cystic Fibrosis gene in 1989, researchers have known that CF results from mutations in the gene for the protein cystic fibrosis trans-membrane conductance regulator (CFTR). Without functioning CFTR, which is an epithelial ion channel, patients have flawed regulation of salt and water absorption and secretion in the lung, liver, pancreas, intestine and reproductive tract. The majority of people with CF in the United States have a specific CFTR mutation, but there are over 1,500 mutations that can cause this multi-system disease, by affecting either the quantity or the quality of CFTR. Approximately 3-5% of patients with Cystic Fibrosis have a missense mutation, G551D, which causes the CFTR protein at the cell surface not to open and close properly.

The question, then: is it possible to change the function of this protein channel itself? In a new report appearing in the FASEB Journal, the researchers describe how they used HT screening to identify small-molecule drug candidates which are able to correct the defects in cystic fibrosis cells, making the cystic fibrosis cell look more like the normal cell.

What is a Peptide Library?

admin — Wed, 17 Aug 2011 20:09:25 +0000

The combinatorial peptide library is a powerful method in which a vast number of various peptides are synthesized.

The first use of synthetic peptide libraries was reported by Geysen et al. in 1984, using the pin method, and since then many papers describing different methods of synthesizing and screening peptide libraries have been published.

The combinatorial peptide library approach is mainly based on three methods. In one, peptide libraries are synthesized and cleaved from a solid support to be screened as free compounds. In a second, synthetic combinatorial libraries of peptides are assayed on their solid support. The third method is based on phage-display, which enables selection of clones of interest rather than screening, because large phage libraries can be panned against a target molecule by standard protocols, allowing enrichment of only a few hundred specific phages that can easily be screened for positive ligands in a single test. Specific phages are then treated for DNA sequencing and peptide genes are revealed for subsequent chemical synthesis.

The above three technologies for selection of peptide ligands fall into two groups: libraries that allow the selection of ligands in their final unlabeled and soluble form and those by which peptides are selected while still linked to their support, either synthetic or biological, or to a labeling molecule.

Synthetic combinatorial libraries, especially synthetic peptide libraries, are generally prepared by two different methods, the “divide, couple, recombine” (DCR) method, also referred to as “pool/split, portion/mix, split-and-mix”, and the “amino acid mixture” method. The DCR method involves dividing resin into pools, coupling amino acids to individual aliquots of resin, mixing them and dividing them for next amino acid coupling. This process generates “one-bead one-compound (OBOC)” libraries containing millions of random peptides, each bead expressing only one peptide and each peptide having equal distribution in the library.

The advantage of the OBOC technique – a large number (10⁶−10⁸) of peptides can be synthesized and screened rapidly. One major disadvantage of the OBOC technique – each library compound is tethered to the solid support via a linker such as polyethylene glycol and may result in steric hindrance between the cellular receptor and the library substance.

Histone deacetylase inhibitors

admin — Sat, 14 Aug 2010 11:49:19 +0000

Histone deacetylases (HDACs) are enzymes that catalyze the deacetylation of lysine residues located in the NH2 terminal tails of core histones, which is associated with transcriptional silencing. There are 18 known human histone deacetylases, grouped into four classes based on the structure of their accessory domains. Class I (HDACs 1-3 and 8), II (HDACs 4-7, 9, and 10), and IV (HDAC 11) enzymes are Zn2+-dependent enzymes and are called HDACs, while class III enzymes (also known as sirtuins) are defined by their dependency on NAD+.

Histone deacetylase inhibitors (HDACis) are emerging as a new class of anticancer drugs and have been shown to alter gene transcription and exert antitumor effects such as growth arrest, differentiation, apoptosis, and inhibition of tumor angiogenesis.

The interest in HDAC inhibitors began almost 30 years ago during some studies designed to understand why DMSO caused terminal differentiation of murine erythroleukemia cells. This early observation paved the way for the development of novel pharmacological agents in the field of chromatin remodeling. In October 2006 the FDA approved the first HDAC inhibitor – Suberoylanilide Hydroxamic Acid (SAHA, Zolinza, Vorinostat) to treat the rare cancer cutaneous T-cell lymphoma (CTCL).

One of the most well-known HDAC inhibitors is a drug called suberoylanilide hydroxamic acid (SAHA)

Based on their chemical structure, histone deacetylase inhibitors inhibitors can be subdivided into four different classes, including hydroxamates, cyclic peptides, aliphatic acids and benzamides. TSA, a compound of hydroxamates, is the first nature product that has been discovered to possess the HDAC inhibitor activity in 1990. Other compounds, for example, CBHA and Panobinostat, have been used in pre- and clinical trials in this group. Another class of HDAC inhibitors is aliphatic acid, including Valproic acid (VPA), phenylbutyrate. The third group is benzamide consisted of Entinostat and MGCD0103. The last group is cyclic peptide including FK-228.

The following HDAC Inhibitors are currently undergoing clinical trials:
Tacedinaline (CI-994, PD-123654, GOE-5549, Acetyldinaline); Entinostat (SNDX-275, MS-27-275, MS-275); BML-210; M344; Dacinostat (LAQ824,NVP-LAQ824); Panobinostat (LBN-589, LBH589, Panobinostat, LBH-589, NVP-LBH589); Mocetinostat (MGCD-0103); Belinostat (PX105684, PXD101); CBHA; PCI-24781 (CRA-024781); ITF2357; Trichostatin A; Apicidin; CUDC-101; Droxinostat; JNJ-26481585; MC1568; SB939; Tubastatin A.

HDAC inhibitors are promising new targeted anti-cancer agents. These substances cause cancer cell growth arrest, differentiation, apoptosis and cell death of a broad spectrum of malignant cells, both solid tumors and hematologic malignancies. Normal cells are much less sensitive to HDAC inhibitors than transformed cells.

References:
1) Jiahuai Tan, et al. Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents. Journal of Hematology & Oncology 2010, 3:5
2) Philip Jones, et al. A Novel Series of Potent and Selective Ketone Histone Deacetylase Inhibitors with Antitumor Activity in Vivo. Journal of Medicinal Chemistry, 2008, 51, 2350–2353.
3) Nancy Zhou, et al. Discovery of N-(2-Aminophenyl)-4-[(4-pyridin-3-ylpyrimidin 2-ylamino)methyl]benzamide (MGCD0103), an Orally Active Histone Deacetylase Inhibitor. Journal of Medicinal Chemistry, 2008, 51, 4072–4075
4) Marielle Paris, et al. Histone Deacetylase Inhibitors: From Bench to Clinic. Journal of Medicinal Chemistry, 2008, 51(6), 1505-29.

What is a Compound Library?

admin — Wed, 14 Jul 2010 18:02:17 +0000

A compound library is a collection of real stored chemicals and/or virtual chemical compounds. The compound library or chemical library can contain stored chemicals each of them has associated data with information such as the chemical structure, purity, quantity, and physiochemical characteristics of the compound. The virtual compound libraries consist of 2D or 3D representations of chemical compounds that are used for diverse purposes using computational methods.
The logical designs of both library types are often similar to one another, and the two methods — experimental (for real compound libraries) and computational (for virtual compound libraries) are often complement one another in drug discovery development process.
What is a purpose of a compound library?
Compound libraries usually used for drug discovery high-throughput screening, a process consisting of testing a large number of chemicals against some assays and/or targets.
Both real and virtual compound libraries are commonly run in parallel in drug discovery campaigns with the results of one compared to the other. The main purpose is to design libraries for promising new drug leads. 20 years ago, the first libraries typically included huge amounts of small-molecule structures; today compound libraries design is more sophisticated than in the past and centers around the methods used for choosing compound membership. The choice of compounds is often based on two widely used design strategies: diversity oriented design and target oriented design. The goal of diversity oriented design strategy is to generate libraries with a highly diverse set of chemical compounds based for example on skeletal diversity, a strategy where the scaffold elements of chemical compounds are chosen to maximize their variation in 3D structure, electrostatics, or molecular properties. A molecular property diversity method include hydrogen bond donors/acceptors, polarizable groups, charge distributions, hydrophobic and lipophobic fragments, and numerous other properties. The diversity of the libraries resulting from these methods is often measured using statistical techniques, such as cluster and principal components analysis. In contrast to diversity, target oriented design seeks to create libraries that are focused around specific chemotypes, molecular species, or classes of compounds. Compound libraries with target oriented design results in focused libraries with a limited number of well-defined structures. To generate focused libraries 3D shape, 3D electrostatics, pharmacophore models, molecular descriptors, and target active sites are used.
Regardless of diversity or target oriented design chemical compounds need to satisfy a variety of constraints before they become marketable drugs, for instance, Lipinski’s rules place limits on molecular weight, the number of hydrogen bond donors and acceptors, the number of rotatable bonds, and solubility. Applying Lipinski’s rules in library design acts as a molecular property filter, you can effectively restrict the set of compounds to those with drug-like characteristics.