Drug Design Reviews - Online (Discontinued) - Volume 2, Issue 6, 2005

Recent advances in computation-based protein engineering offer opportunities to introduce or modify the biophysical characteristics of proteins at will. The power of computational design comes from the ability to surpass the combinatorial and physical limitations inherent to laboratory-based high-throughput or trial-and-error methods. As a result, modifications that require significant changes to the amino acid sequence of a protein are now accessible to the protein engineering community. Hydrophobic cores of proteins have been repacked to increase their thermostability. Binding sites in proteins have been modified to increase affinity or alter specificity for proteins, peptides, and small molecules. Enzymes have been designed de novo. Non-natural protein folds have been created. For the most part, these achievements have been applied to proteins that make good model systems in academic settings. How can these computational methods be applied to therapeutically relevant proteins? This review will focus on the ground-breaking achievements of computation-based protein engineering and on recent applications of rational design to improve therapeutic proteins.

Tuberculosis (TB) is a growing international health concern and the appearance of multidrug-resistant (MDR) TB has greatly contributed to the increased incidence of TB. Because of the increasing rate of MDR-TB and the high rate of a co-infection with HIV, the development of potent new anti-TB drugs without cross-resistance with known antimycobacterial agents is urgently needed. This article deals with the following areas. First, the future development of new antitubercular drugs is discussed according to the potential pharmacological targets. New critical information on the whole genome of Mycobacterium tuberculosis (MTB) recently elucidated and increasing knowledge on various mycobacterial virulence genes will promote the progression in the identification of genes that code for new drug targets. Using such findings on MTB genome, drug development using quantitative structure-activity relationship may be possible in the near future. In this review, I describe the drug targets for development of new classes of drugs, especially those active against dormant types of MTB. Second, I will review the drug vehicles which enable efficacious drug delivery to their target in vivo. The usefulness of liposome and microsphere technologies, which enable the encapsulated drugs to deliver the requested doses of them for prolonged time periods by a single shot without causing any toxicity and, moreover, enable the highly targeted delivery of the drugs to host macrophages, is discussed.

Genomics projects elucidating the molecular mechanisms of osteoarthritis are complicated by the simultaneous appearance of many different and in part contrary pathways in diseased cartilage. To view a potential function of genes being differentially expressed in osteoarthritis, it has proven extremely useful to investigate their expression patterns in the developing skeleton. There, counteractive processes such as cartilage synthesis and degradation are separated in a spatio-temporal manner. Accordingly, expression analysis of osteoarthritis-relevant genes on developing skeletal tissues can provide early evidence for a potential pathway in which they may function. For pharmaceutical treatment of osteoarthritis, inhibition of cartilage degradation by inactivation of proteolytic enzymes, or stimulation of anabolic activities for cartilage restoration and neosynthesis are the two major logical approaches. For both aspects molecular concepts have been developed which are strongly supported by developmental studies. Gene targeting in mice has provided important information about the impact of individual matrix metalloproteinases (MMPs) in osteoarthritic cartilage degradation, as well as the essential role of Sox transcription factor family members in cartilage anabolism. On the basis of these studies, powerful developmental tools are available to study the in vivo efficacy of MMP inhibitors and to develop drugs to restore cartilage function in patients with osteoarthritis.

Memantine is an uncompetitive antagonist with moderate affinity for NMDA receptors, and it demonstrates voltage-dependency and relatively fast on/off receptor kinetics. Agents such as memantine which mimic some of the features of the endogenous antagonist magnesium may be an optimal treatment combining both neuroprotective activity with symptomatological improvement. The latter can be explained on the basis of a decrease in the noise level and restoration of a sufficient "signal to noise" ratio. Memantine protects cultured neurons from excitotoxin-induced cell-death. The drug dose-dependently prevented glutamate-induced cell death in rat cerebellar, cortical, mesencephalic and hippocampal neurons and calcium ion-induced death in retinal ganglions obtained from rats. Memantine exerts neuroprotective effects in several models of brain injury. The drug attenuated loss of cholinergic neurons in the CNS induced by injection of NMDA into the basal forebrain of rats. At a dosage of 5-10 mg/kg in rats, memantine induced production of brain-derived neurotrophic factor (BDNF), a substance shown to promote survival and differentiation of CNS neurons. Due to the preclinical effects of memantine brought about by its anti-ischemic and anti-excitotoxic properties, recent clinical efficacy has been demonstrated in patients with advanced dementia of vascular origins. We will discuss the role, the potential benefits and the results obtained in the field.

Mannose-binding lectin (MBL) has attracted great interest as potential target for passive immunotherapy to prevent or reduce infection in a variety of clinical settings. MBL is a multimeric serum lectin that recognises a broad array of pathogens and initiates complement activation independently of antibody. MBL2, the gene encoding MBL, contains several polymorphisms that influence synthesis, assembly or stability of functional multimeric MBL. Genetically determined MBL deficiency is present in up to 40% of individuals, with up to 8% having profoundly reduced circulating MBL levels. MBL deficiency is usually clinically silent in otherwise healthy individuals, but is associated with the risk and severity of infection when immunity is already compromised. This review provides an overview of the basic biology and genetics of MBL, reviews data regarding MBL disease associations, and discusses the potential clinical utility of MBL replacement therapy.

Drug design is a complex process that requires a good command of several disciplines including organic and physical chemistry, biochemistry and metabolism, pharmacology, pharmacodynamics and pharmacokinetics. The process starts with the synthesis of compound libraries and their evaluation toward pharmacological targets for biological activity. This first step allows to identify lead compounds characterized by a desired pharmacological activity. However, such identified compounds may have undesirable characteristics that limit their bioavailability, structural features that adversely alter their metabolism, display toxicity or possess unwanted side effects. Converting a pharmacological lead into a successful drug constitutes a major challenge for pharmaceutical laboratories. Among the approaches used to transform lead compounds into safer and clinically relevant agents, the bioisosteric substitution constitutes a key tool at the medicinal chemist disposal. Classical bioisosteres have similar steric and electronic characteristics and have the same number of atoms than the element or substituent for which they are used as a replacement. One of the most common classical bioisosteric substitution is the incorporation of fluorine into a compound in replacement of specific hydroxyl groups or hydrogens atoms. A less well-known classical bioisostere is the replacement of a carbon by a silicon atom (silasubstitution). The silicon bioisostere offers interesting benefits in drug design. The altered bond length and angles of silicon over carbon in a new chemical entity can lead to its improved pharmacological potency, modify its selectivity toward a given target, or change its metabolic rate, respectively. The sila-substitution can also increase the lipophilicity of a compound and hence increase its tissue distribution, particularly through membranes including the blood brain barrier, although with the limitation of a decreased water solubility. This review will present the synthetic methods currently available to effect a sila-substitution, along with its advantages and limitations in drug design. The discussion will be extended to practical examples of compounds currently in clinical trials.