Mini Reviews in Medicinal Chemistry - Volume 8, Issue 3, 2008

P-glycoprotein (Pgp, ABCB1) is an efflux transporter for a variety of amphipathic agents that can affect the pharmacokinetics of drugs. In order to extrapolate transport and pharmacokinetic data of the drug candidates obtained from in vitro and animal models to those in humans, it is important to understand the functional differences of Pgps from various mammalian species including human, monkey, dog, rat, and mouse. Here, we review differences/similarities in the properties of Pgp from numerous mammalian species commonly used in preclinical studies and discuss their relevance to the pharmacokinetics of potential drug molecules.

Drug combination therapies have been devised to delay the development and spread of resistant malaria parasites. However, poor design often leads to ineffective combinations. Here, the properties of various drug combinations are reviewed in relationship to drug resistance and their pharmacokinetic compatibility.

Sometimes the complexity of a system, or the properties derived from it, do depend neither on the individual characteristics of the components of the system nor on the nature of the physical forces that hold them together. In such cases the properties derived from the “organization” of the system given by the connectivity of its elements can be determinant for explaining the structure of such systems. Here we explore the necessity of accounting for these structural characteristics in the molecular descriptors. We show that graph theory is the most appropriate mathematical theory to account for such molecular features. We review a method (TOPS-MODE) that is able to transform simple molecular descriptors, such as logP, polar surface area, molar refraction, charges, etc., into series of descriptors that account for the distribution of these characteristics (hydrophobicity, polarity, steric effects, etc) across the molecule. We explain the mathematical and physical principles of the TOPS-MODE method and develop three examples covering the description and interpretation of skin sensitisation of chemicals, chromosome aberration produced by organic molecules and drug binding to human serum albumin.

After spinal cord injury, a number of destructive events developed immediately after the primary insult increase tissue damage. Several therapeutic approaches are directed to neutralize these phenomena. The present manuscript revises diverse pharmacological treatments used to promote neuroprotection, both in clinical and experimental acute spinal cord injuries.

APOBEC3G (apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G) was identified as an anti- HIV-1 (human immunodeficiency virus type 1) cellular factor in target CD4 T cells. It is a member of the APOBEC family of cytidine deaminases consisting of APOBEC1, APOBEC2, APOBEC3 (A to H), and AID (activation induced deaminase). During reverse transcription, it deaminates dC to dU in nascent minus-strand viral DNA, resulting in G-to-A hypermutation in the plus strand DNA to inhibit the replication of HIV-1. On the contrary, HIV-1 Vif protein counteracts this enzyme by the ubiquitin-proteasome pathway to enable HIV-1 replicate in target cells. Vif forms an E3 ligase complex with cellular proteins including Cullin5, ElonginB, and ElonginC (Vif-BC-Cul5) and functions as a substrate recognition subunit of the complex to target APOBEC3G for ubiquitin-proteasome dependent degradation in virus-producing cells. APOBEC3G has also been shown to have a broad antiviral activity on a wide variety of viruses which include not only retroviruses such as other lentiviruses, murine leukemia virus (MLV), and human T-cell leukemia virus type 1 (HTLV-1) but also other viruses such as hepatitis B virus (HBV) and adeno-associated virus. Furthermore, other members of the APOBEC family also show a broad antiviral activity, but target virus specificities vary among APOBEC members. On the other hand, viruses have their own mechanisms to escape from APOBEC. These expanding evidences suggest that the APOBEC family of cytidine deaminases plays an important role in antiviral innate immunity and might be a novel target for an antiviral therapy. Here we review the present understanding of APOBEC3 proteins as an antiviral innate immunity and battles between APOBEC3 and viruses.

Orotidine 5'-monophosphate decarboxylase (ODCase) is among the most proficient enzymes, and catalyzes the decarboxylation of OMP to UMP. An overview of ODCase and various proposals for its catalytic mechanism of decarboxylation are briefly presented here. A number of inhibitors of ODCase and new developments in the X-ray structures of ODCases from different species are discussed in the context of their therapeutic potential against cancer and infectious diseases. Latest discoveries in the inhibition of ODCase, for example using the novel C6 substitutions on the uridine, open new doors for drug discovery targeting parasitic diseases such as malaria.

A better understanding of the mechanisms involved in small interference RNA (siRNA) gene silencing opens new horizons for the development of the targeted therapy of malignant and benign diseases. As a research tool, siRNA has proven to be highly effective in silencing specific genes and modulating intracellular signaling pathways. However, systemic delivery of siRNA has been more problematic due to degradation and poor cellular uptake. In order to overcome these limitations, a variety of strategies are being developed including new delivery vehicles and chemical modifications. Here, we review potential approaches for the systemic delivery of siRNA for cancer treatment.

HPLC is discussed as an essential tool in medicinal chemistry for the monitoring of tricyclic antidepressants in biofluids, providing clinicians with efficient fast and reliable methods to define individual optimum therapeutic concentrations in treatment of depressions. Additional information on mechanism of action, structure activity relationship and metabolism is provided.

The marine polyketide discodermolide is a member of a class of natural products that stabilize microtubules. Many analogues have been synthesized suggesting that few changes can be made to the internal carbon backbone. Both ends of the molecule, however, can be modified. The majority of analogues have been generated via modification of the lactone region. This suggests that significant simplifications can be made in this region provided that the lactone moiety is maintained.

Attempts have been made to find specific antigens for a novel NKT cell subset bearing invariant Vα19-Jα33 TCR α chains (Vα19 NKT cell). Comprehensive examinations revealed substantial antigenic activity in synthetic α- mannosylceramide (ManCer) that was presented by MR1. Structural modification of the sphingosine moiety of α-ManCer improved antigenic activity to enhance either Th1 or Th2 -promoting cytokine production by Vα19 NKT cells. Such α- ManCer analogues will be useful for developing new therapies as immunomodulators.

Anthrax lethal factor (LF), mitogen-activated protein kinase kinase (MAPKK), small molecular weight inhibitors, structure-based drug discovery, zinc-metalloprotease.