Mini Reviews in Medicinal Chemistry - Volume 9, Issue 4, 2009

Tuberculosis has remained an enemy of humankind since its inception. It has affected all facets of human life and remained leading cause of mortality and morbidity despite of availability of effective chemotherapy and BCG vaccine in 21st century. This has exposed the frailties of the current drug armamentarium. No new drug is available acting through novel mechanism of action for last 40 years. This has culminated into resistant strain of TB, MDR-TB and XDR-TB. Concomitant occurrence of TB and HIV presents a lethal combination. The availability of the M. tuberculosis genome sequence and mycobacterial genetic tools, such as transposon mutagenesis, gene knockout and gene transfer, greatly facilitate target identification. This review provides a comprehensive literature compilation on the present research paradigm of anti-TB drug discovery including advances in the new structural classes analogs reported in last decade.

We described chemical inhibitors of Mos1 transposition. Some were already known to affect a related prokaryotic transposase (Tn5) or HIV-1 integrase, whereas the other were new compounds in this field. The new compounds were all organized around a bis-(heteroaryl)maleimides scaffold. Their mechanism of action depended on the chemical substitutions on the scaffold. The cross-activity, between HIV-1 integrase and Mos1 transposase, of the new group of inhibitors showed that Mos1 transposase could constitute an excellent surrogate HIV-1 inhibitor screen.

This review compiles the scientific basis to propose the pleiotrophin/receptor protein tyrosine phosphatase β/ζ signaling pathway as a new therapeutic target to prevent drug of abuse-induced toxicity. In addition, potential guidelines are provided for the development of new therapeutic compounds derived from that knowledge. This approach may be relevant since efficient therapeutic strategies are currently lacking in this field, even when drug-induced neurotoxicity seems to underlie the neurodegenerative disorders diagnosed in drug addicts.

The endocannabinoid system, including endogenous ligands (‘endocannabinoids’ ECs), their receptors, synthesizing and degrading enzymes, as well as transporter molecules, has been detected from the earliest stages of embryonic development and throughout pre- and postnatal development. ECs are bioactive lipids, which comprise amides, esters and ethers of long chain polyunsaturated fatty acids. Anandamide (N-arachidonoylethanolamine; AEA) and 2- arachidonoylglycerol (2-AG) are the best studied ECs, and act as agonists of cannabinoid receptors. Thus, AEA and 2-AG mimic several pharmacological effects of the exogenous cannabinoid delta9-tetrahydrocannabinol (Δ9-THC), the psychoactive principle of cannabis sativa preparations like hashish and marijuana. Recently, however, several lines of evidence have suggested that the EC system may play an important role in early neuronal development as well as a widespread role in neurodegeneration disorders. Many of the effects of cannabinoids and ECs are mediated by two G proteincoupled receptors (GPCRs), CB1 and CB2, although additional receptors may be implicated. Both CB1 and CB2 couple primarily to inhibitory G proteins and are subject to the same pharmacological influences as other GPCRs. This new system is briefly presented in this review, in order to put in a better perspective the role of the EC pathway from neurodevelopment to neurodegenerative disorders, like Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. In addition, the potential exploitation of antagonists of CB1 receptors, or of inhibitors of EC metabolism, as next-generation therapeutics is discussed.

Polysaccharides and other cationic polymers have been recently used in pharmaceutical research and industry for their properties to control the release of antibiotics, DNA, proteins, peptide drugs or vaccines. They have been also extensively studied as non viral DNA carriers for gene delivery and therapy. Chitosan is one of the most used since it can promote long-term release of incorporated drugs. Here, we reviewed the recent literature on the preparation of chitosan micro- and nanospheres using different manufacturing processes (nanofabrication). Moreover, the preparation of chitosan and chitosan/DNA nanospheres using a novel and simple osmosis-based method has been recently reported. This novel nanofabrication method may be a useful alternative to obtain small DNA-containing nanospheres (38 ± 4 nm) for biomedical applications. The reported method has general applicability to various synthetic or natural biopolymers. Solvent, temperature and membrane cut-off are the physicochemical parameters able to control the overall osmotic process leading to obtain several nanostructured systems with different size and shape that may be used in several biotechnological applications.

Investigations into the immunogenicity of the prion protein are ongoing. To combat its pathological isoform without affecting the cellular protein is a challenge in prion research. We here summarize the studies in which prion protein peptides have been used for immunization, to thus determine the most immunogenic parts of the prion protein.

This is a review of classical and novel concepts of drug delivery in particular diseases such as central nervous system disease, ophthalmic disease, cardiovascular disease, cancer and others. Nowadays, scientists are trying to propose efficient and selective drugs for the site of action, with best acceptance of patients, that can be metabolized to non-toxic derivatives. Prodrugs, soft drugs, codrugs are designed to maximize the amount of active drugs that reaches the site of action, through changing the physicochemical, biopharmaceutical or pharmacokinetic properties of the parent drugs. For last years different concepts of drug delivery have been developed to achieve the best patients’ tolerance of a drug that has no undesirable properties. It is established that future studies will ameliorate drug properties so as to achieve the best drug delivery system.

Although the role of serine/threonine protein kinase C (PKC) in malignant transformation is known from decades, an anti-PKC based approach in cancer therapy was hampered for the difficulties in developing pharmacological compounds able to selectively inhibit specific PKC isoforms. In this review, the role of PKC-η and PKC-δ in promoting and counteracting tumor progression in different types of cancer, respectively, will be discussed in relationship with promising therapeutic perspectives based either on small molecule inhibitors or on natural compounds. Among a miriad of molecules able to modulate PKC activity, we will focus on the role of the enzastaurin and briostatin-1, which already entered clinical trials for several human cancers.

The capsid (CA) protein is the major structural component of HIV-1 and plays a key role in the regulation of viral life cycle. Inhibition of CA will affect the viral assembly and budding processes, causing decreased viral infectivity. This review describes the structure and function of the HIV-1 CA and latest progress in the discovery of HIV-1 CA inhibitors.