Current Pharmaceutical Design - Volume 19, Issue 10, 2013

Acquired Immune Deficiency Syndrome (AIDS), an immuno-compromized condition, a sequel to untreated human immunodeficiency virus (HIV) infection, inviting several life-threatening diseases, has become one of the most fatal disorders in the recent past because of HIV strain variance due to mutations, passive latency and reservoirs helping in replenishing and reviving the HIV-1 proviral DNA. Scientific efforts have led to the discovery of several effective drugs against HIV and lowered the morbidity and mortality all over the world. However, despite availability of a good number of anti-HIV drugs, the problem, for the foreseeable reasons, stands out as the most chronic disease due to the less tolerability and low accessibility of drugs, life-long expensive treatment, and above all, the emergence of drug resistant viral strains. This review dwells upon HIV infection and its proliferation inside the host system, drug targets, different types of drugs, their structural features and mode of interaction with viral targets and drug regimens. It further focuses on topics of latest interest regarding drug development, fixed dose combinations (FDCs), the limitations of present day drugs with their structural features along with their pharmacodynamics, pharmacokinetics and pharmacogenomics and the challenges in finding a permanent cure for HIV/AIDS.

Since the discovery of human immunodeficiency virus (HIV) as a causative agent of acquired immune deficiency syndrome (AIDS) various strategies were employed to counter its devastating actions. One such concept relies on the prevention of HIV entry into host's “competent” cells by means of compounds known as entry inhibitors. HIV entry inhibitors comprise a group of immensely diverse compounds ranging from proteins/antibodies to small organic molecules and capable of targeting various stages of viral entry. Although already in clinical use, this approach to HIV therapy is still being investigated to produce new promising antiviral compounds. Here, we review the latest advances in this area.

Fusion of viral and cellular membranes is an essential step for HIV-1 infection. This process offers an attractive target for developing antiviral agents. T20 (Enfuvirtide, Fuzeon), a 36-amino acid peptide derived from the C-terminal heptad repeat region of HIV-1 gp41, is the first and only clinically approved HIV-1 fusion inhibitor that being used for treatment of HIV/AIDS patients failed to respond to current antiretroviral drugs. However, T20-resistance can be acquired rather easily in vitro and in vivo. T1249 is considered as a representative of the second generation fusion inhibitors, but its clinical evaluation was halted due to the problem of drug formulation. To overcome these challenges, a number of strategies have been applied to develop the third or next-generation inhibitors with the significantly improved antiviral activity and pharmacokinetic profiles. Promisingly, several peptides are currently under clinical trials, such as Sifuvirtide and VIR-576. Recently, several high resolution crystal structures of HIV-1 fusion inhibitor peptides were reported, which reveal the key residues or motifs underlying their potency against diverse HIV-1 variants. This review highlights the development of the representative peptide inhibitors of HIV-1 fusion toward providing some insights into the future of this class of anti-HIV drugs.

HIV-1 membrane fusion as a part of the process of viral entry in the target cells is facilitated by gp41 and gp120, which are encoded by Env gene of HIV-1. Based on the structure and the mechanism researches, new treatment options targeting HIV-1 entry process have been proposed. Enfuvirtide, which mimics amino acid sequences of viral envelope glycoprotein gp41, is the first HIV-1 fusion inhibitor approved by FDA. Although it fulfills vital functions by binding to gp41 and abolishing the membrane fusion reaction when used in combination, it could induce drug resistant virus variants. Currently, a number of design and modification schemes have been presented, a large number of prospective fusion peptides have emerged. For these fusion inhibitors, multiple mutations in gp41 have been associated with the loss of susceptibility to agents. This review reported the current developments and innovative designs of HIV-1 membrane fusion inhibitors.

Gp41 is regarded as an attractive target for development of HIV-1 entry inhibitors since it mediates the fusion process of HIV- 1 entry into the target cell through the six-helix bundle (6-HB) formation between its N-heptad repeat (NHR) and C-heptad repeat (CHR). Any chemical entity that disrupts the six-helix bundle formation may inhibit the fusion process, thereby blocking HIV-1 entry into the target cells. A brief review of discovering small molecule inhibitors targeting gp41 is presented here, including the development of assay methods, current known small molecule inhibitors and their binding mode studies. Lessons learned and challenges remained in view of blocking protein-protein interaction between NHR and CHR are also discussed.

Human immunodeficiency virus type 1 (HIV-1) primarily infects and then destroys CD4-positive lymphocytes, leading to the acquired immunodeficiency syndrome (AIDS). Over 20 drugs, most small and orally bioavailable, have been approved, and include reverse transcriptase and protease inhibitors. In 2003, the US-FDA approved enfuvirtide (T-20), a 36-amino acid peptide derived from the C-terminal heptad repeat of the HIV-1 gp41 ectodomain. T-20 was initially identified in 1992 from biological studies, and can effectively suppress HIV-1 infection with multi-drug resistance. Currently, numerous fusion inhibitory peptides have been designed and synthesized. Some of these peptides show strong inhibition even towards HIV-1 strains resistant to T-20. These developments also facilitate basic research into the mechanisms of HIV-1 fusion, because peptide inhibition resembles the process of viral fusion with the cellular membrane. In this review, we focus on HIV-1 fusion inhibitors and the application of their development and clinical findings to the concept of "biology to chemistry" to support rational drug design for small bioavailable compounds.

HIV integrase became an important target for drug development more than twenty years ago. However, progress has been hampered by the lack of assays suitable for high throughput screening, a reliable crystal structure or pharmacophore. Thus, a real breakthrough was only observed in 2007 with the introduction of the first integrase inhibitor, raltegravir, into treatment. To date, the armament of integrase inhibitors is broad and covers several drugs from different classes that are under clinical trials. Among them, quinoline-based compounds and analogues occupy an important place. This review is focused on those compounds that have a quinoline scaffold and attempts to answer the question of whether quinoline is privileged for these activities. In fact, quinoline has been claimed as a privileged structure several times for different fields of activities. A closer look at its structural features may reveal the prerequisites responsible for the popularity of quinoline-based inhibitors of HIV integrase.

The HIV-1 reverse transcriptase (RT) is one of the most attracting targets for the development of early phase infection inhibitors. Although many RT inhibitors have been approved for the treatment of HIV-1 infection, they all target the polymerase function of this enzyme. So far, no drugs are available for the inhibition of the RT associated ribonuclease H function (RNase H), which plays an essential role in the HIV replication cycle. Moreover it should be reported that many of the known RT inhibitors, targeting the polymerase function, enhance the RNase H activity, indicating that, although spatially distinct, a close relation occurs between the two functions. The aim of this review is to summarise the efforts in the design of new inhibitors either characterized by a novel mechanism of action or capable of blocking both RT associated functions, as well as pointing out the main binding features of the known RT inhibitors.

HIV-1 infection can be effectively controlled by HAART, which improves the quality of lives of infected individuals, but fails to completely eradicate the virus, even after decades of treatment. This issue, together with the emergence of multi-drug-resistant viruses, clearly underscores the continuing need to find novel agents able to target vulnerable steps in the viral replication cycle. HIV transcriptional regulation is a crucial step required to re-initiate viral replication from post-integration latency after interruption of therapy and to keep the virus in circulation. In this step, the viral protein Tat plays a central role by dramatically increasing the production of elongated transcripts through its unique interaction with the viral TAR RNA and the cellular cofactor P-TEFb, together with a myriad of other host factors which are recruited to the viral promoter to ensure efficient transcription. The transcriptional machinery, involving an intricate interplay of many viral and cellular components, offers a plethora of potential therapeutic targets that have not yet been exploited by any of the antiretroviral drugs used in therapy. In this review we explore the state-of-the-art of Tat-mediated transcription inhibitors which target the well-consolidated Tat/TAR/PTEFb axis, together with novel therapeutics that interfere with various host-cell factors, including some pioneer inhibitors designed on the basis of recent molecular and structural studies.

Branched sugar nucleosides have attracted much attention due to their biological activities. We have demonstrated that epoxysugar nucleosides serve as versatile precursor for the stereo-defined synthesis of these nucleoside derivatives on the basis of its ring opening with organoaluminum or organosilicon reagents. In this review article, novel methods for the synthesis of nucleoside analogues branched at the 1' and 4'-position will be described. During this study, we could discover an anti-HIV agent, 4'-ethynylstavudine (Festinavir). Festinavir showed more potent anti-HIV activity than the parent compound stavudine (d4T). Other significant properties of Festinavir are as follows: 1) much less toxic to various cells and also to mitochondorial DNA synthesis than d4T, 2) better substrate for human thymidine kinase than d4T, 3) resistant not only to chemical glycosidic bond cleavage but also to catabolism by thymidine phosphorylase, 4) the activity improves in the presence of a major mutation, K103N, associated with resistance to non-nucleoside reverse transcriptase inhibitors. Detailed profile of the antiviral activities, biology and pharmacology of Festinavir are also described.

Background: A growing body of evidence suggests that glutamatergic system, especially the abnormalities of glutamate and N-methyl-D-aspartate (NMDA) receptors contribute to the pathophysiology of major depressive disorders. An imbalance in glutamatergic neurotransmission may contribute to increased levels of NMDA agonism, thereby enhancing excitatory activity in most brain circuits involved in major depression. Although NMDA receptor antagonists have been demonstrated to possess antidepressant-like activity, the molecular changes underlying abnormal glutamatergic signaling still remain poorly understood. Therefore, we aimed to review the current literature focusing on the main pharmacological properties and the impact of glutamatergic drugs targeting NMDA receptors in major depression. Methods: A detailed literature search in PubMed/Medline and ScienceDirect databases using the terms glutamate, depression and major depressive disorder has been performed. Results: Most drugs acting at glutamatergic receptors showed biochemical effects indicative of antidepressant activity in both clinical and preclinical studies. Recent neuroimaging and genetic contributions also confirm the antidepressant properties of these medications. However, human studies including NMDA receptor antagonists provided mixed results. In overall, glutamatergic receptor modulation may facilitate neuronal stem cell enhancement (neurogenesis) as well as the release of neurotransmitters associated with treatment response to depression in humans. Limitations: Cognitive side effects and psychotomimetic properties complicate the application and the development of clinically useful agents. Conclusions: Glutamatergic system represents a target for effective intervention in major depression. Specifically, those glutamatergic medications targeting NMDA receptors by inhibiting the release of neurotransmitters or modulating its post-synaptic responses may serve as molecule modulators with specific antidepressant properties.

Tubulin protein is a highly imperative and feasible goal for anticancer drug discovery. Hundreds of naturally occurring, semi synthetic and synthetic antitubulin agents have been reported till now. Among these, Combretastatin A - 4 (CA - 4) is effective antimitotic agent possessing potent cytotoxicity against a panel of cancer cells, including multi-drug resistant cancer cell lines. The inadequate water solubility and inactivation of these analogs during storage limit their use as clinical anticancer agents. To overcome these shortcomings, numerous water soluble amino analogs, amino acid derivative, phosphate prodrug (CA - 4P) and cis-locked CA - 4 have been developed with distinctive attributes of antitubulin and antivascular properties in a wide variety of preclinical tumor models. Subsequently, several heterocycle based cis restricted CA - 4 analogs are being reported for antitumor activity against collection of cancer cell lines. This review recapitulates the rational design, structure activity relationship, pharmacokinetic and pharmacodynamic profile of synthesized cis restricted CA - 4 analogs.

Objective. Rheumatoid arthritis (RA) is a chronic inflammatory disease that damages the synovial joints, and patients with it are often anorexic and cachectic with high morbidity and mortality. Biological therapy with anti-tumor necrosis factor (TNF)-α has been proven effective as a treatment for RA. However, the long-term effects of anti-TNF-α therapy on body weight, appetite, plasma gut hormones and leptin have not been investigated. Methods. Twenty RA patients received subcutaneous injections of etanercept, a chimeric protein of human IgG1 Fc and TNF receptor p75, twice weekly for 12 consecutive months. Sequential changes in body weight, body fat, appetite rating, lipid profiles, gut hormones and leptin were measured at baseline and at 3 and 12 months after treatment. Ten RA patients who received non-biological disease modifying anti-rheumatic drugs were enrolled as the controls and were appraised at baseline and at 12 months after treatment (a nonrandomized study). Results. Significant weight gain, hyperuricemia, decreased fasting plasma glucose-dependent insulinotropic polypeptide (GIP) levels, and loss of post-oral glucose suppression of plasma leptin concentration were found in the patients after the 12-month course of etanercept therapy, but not in the controls. A transient decrease in fasting plasma acyl ghrelin occurred at 3 months during etanercept treatment. Appetite score and serum lipid profiles did not change in either group. Conclusion. Long-term therapy with anti-TNF-α is promising in ameliorating body mass decrease in patients with active RA. Plasma levels of ghrelin, GIP and leptin may play significant roles in maintaining energy homeostasis in the anti-inflammatory responses during RA remission.