Introduction: Human immunodeficiency virus (HIV) type-1 non-nucleoside and nucleoside reverse transcriptase inhibitors (NNRTIs) are key drugs of highly active antiretroviral therapy (HAART) in the clinical management of acquired immune deficiency syndrome (AIDS)/HIV infection. Discussion: First-generation NNRTIs, nevirapine (NVP), delavirdine (DLV) and efavirenz (EFV) are drugs with a low genetic barrier and poor resistance profile, which has led to the development of new generations of NNRTIs. Second-generation NNRTIs, etravirine (ETR) and rilpivirine (RPV) have been approved by the Food and Drug Administration and European Union, and the next generation of drugs is currently being clinically developed. This review describes recent clinical data, pharmacokinetics, metabolism, pharmacodynamics, safety and tolerability of commercialized NNRTIs, including the effects of sex, race and age differences on pharmacokinetics and safety. Moreover, it summarizes the characteristics of next-generation NNRTIs: lersivirine, GSK 2248761, RDEA806, BILR 355 BS, calanolide A, MK-4965, MK-1439 and MK-6186. Conclusions: This review presents a wide description of NNRTIs, providing useful information for researchers interested in this field, both in clinical use and in research. Keywords: human immunodeficiency virus; non-nucleoside reverse transcriptase inhibitors; nevirapine; delavirdine; efavirenz; etravirine; rilpivirine; next-generation non-nucleoside reverse transcriptase inhibitors. (Published: 4 September 2013) Citation: Usach I et al. Journal of the International AIDS Society 2013, 16 :18567 http://www.jiasociety.org/index.php/jias/article/view/18567 | http://dx.doi.org/10.7448/IAS.16.1.18567

https://onlinelibrary.wiley.com/doi/pdf/10.7448/IAS.16.1.18567

Non-nucleoside reverse transcriptase inhibitors: a review on pharmacokinetics, pharmacodynamics, safety and tolerability.

HIV/AIDS pandemics is a serious threat to health and development of mankind, and searching for effective anti-HIV agents remains actual. Considerable progress has been made in recent years in the field of drug development against HIV. A lot of structurally different coumarins were found to display potent anti-HIV activity. The current review demonstrates the variety of synthetic coumarins having unique mechanism of action referring to the different stages of HIV replication. Recent studies based on the account of various synthetic coumarins seem to indicate that some of them serve as potent non-nucleoside RT-inhibitors, another as inhibitors of HIV-integrase or HIV-protease. The merits of selecting potential anti-HIV agents to be used in rational combination drugs design and structure-activity relationships are discussed.The scientific community is looking actively for new drugs and combinations for treatment of HIV infection effective for first-line treatment, as well as against resistant mutants. The investigation on chemical anti-HIV agents gives hope and optimism about it. This review article describes recent progress in the discovery, structure modification, and structure-activity relationship studies of potent anti-HIV coumarin derivatives.

/pdf/structure-activity-relationships-of-synthetic-coumarins-as-3ydfz2yzfc.pdf

Structure-Activity Relationships of Synthetic Coumarins as HIV-1 Inhibitors

(+)-Calanolide A is a novel, naturally occurring, nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase first isolated from a tropical tree (Calophyllum lanigerum) in the Malaysian rain forest. Previous studies have demonstrated that (+)-calanolide A has specific activity against the reverse transcriptase of HIV-1 and a favorable safety profile in animals. In addition, (+)-calanolide A exhibits a unique HIV-1 resistance profile in vitro. The safety and pharmacokinetics of (+)-calanolide A was examined in four successive single-dose cohorts (200, 400, 600, and 800 mg) in healthy, HIV-negative volunteers. In this initial phase I study, the toxicity of (+)-calanolide A was minimal in the 47 subjects treated. Dizziness, taste perversion, headache, eructation, and nausea were the most frequently reported adverse events. These events were not all judged to be related to study medication nor were they dose related. While 51% of subjects reported mild and transient dizziness, in many cases this appeared to be temporally related to phlebotomy. Calculation of the terminal-phase half-life (t1/2) was precluded by intrasubject variability in the 200-, 400-, and 600-mg dose cohorts but was approximately 20 h for the 800-mg dose group. (+)-Calanolide A was rapidly absorbed following administration, with time to maximum concentration of drug in plasma (Tmax) values occurring between 2.4 and 5.2 h postdosing depending on the dose. Plasma levels of (+)-calanolide A at all dosing levels were quite variable; however, both the mean concentration in plasma (Cmax), and the area under the plasma concentration-time curve increased proportionately in relation to the dose. Although raw plasma drug levels were higher in women than in men, when doses were normalized for body mass, the pharmacokinetic profiles were virtually identical with those observed for males. In general, levels of (+)-calanolide A in human plasma were higher than would have been predicted from animal studies, yet the safety profile remained benign. In conclusion, this study demonstrated the safety and favorable pharmacokinetic profile of single doses of (+)-calanolide A in healthy, HIV-negative individuals.

Safety and Pharmacokinetics of Single Doses of (+)-Calanolide A, a Novel, Naturally Occurring Nonnucleoside Reverse Transcriptase Inhibitor, in Healthy, Human Immunodeficiency Virus-Negative Human Subjects

The use of ethnomedicines to manage HIV/AIDS has recently gained public interest, although harmonization with official HIV/AIDS policy remains a contentious issue in many countries. Plants and other natural products present a large repertoire from which to isolate novel anti-HIV active compounds. In this literature survey, 55 plant families containing 95 plant species, and other natural products, were found to contain anti-HIV active compounds that included diterpenes, triterpenes, biflavonoids, coumarins, caffeic acid tetramers, hypericin, gallotannins, galloylquinic acids, curcumins, michellamines, and limonoids. These active compounds inhibited various steps in the HIV life cycle. However, further studies are needed to determine their interactions with current regimes of antiretroviral drugs. More clinical trials of candidate drugs developed from these novel compounds are also encouraged.

	Key words: Anti-HIV active compounds, other natural products, plants.

Ethnomedicinal plants and other natural products with anti-HIV active compounds and their putative modes of action

Background: (+)-Calanolide A is a naturally occurring nonnucleoside reverse transciptase inhibitor (NNRTI) that exhibits enhanced activity against HIV-1 isolates with the Y181C mutation and retains activity against HIV-1 isolates with dual Y181C and K103N mutations. Previous studies have demonstrated that (+)-calanolide A has a favorable safety profile in both animal and human subjects. Method: In this study, the safety and pharmacokinetics of multiple escalating doses of (+)-calanolide A were evaluated in a total of 47 healthy, HIV-seronegative individuals. Results: All adverse events seen in the study were mild to moderate in intensity and were transient. The most common adverse events seen were headache, dizziness, nausea, and taste perversion (oily aftertaste). Laboratory abnormalities were determined to be clinically insignificant or unrelated to (+)-calanolide A administration. No dose-related pattern in adverse event or laboratory abnormality incidence was apparent. In all cohorts examined,...

Safety and pharmacokinetic profile of multiple escalating doses of (+)-calanolide A, a naturally occurring nonnucleoside reverse transcriptase inhibitor, in healthy HIV-negative volunteers.

Both naturally occurring and semi-synthetic calanolide compounds are potent anti-human immunodeficiency virus (HIV) agents. In fresh human cells, they are highly effective inhibitors against low passage clinical virus strains, including those representative of the various HIV-1 clade strains (A through F), syncytium-inducing (SI) and non-syncytium-inducing (NSI) isolates, and T-tropic and monocyte-tropic isolates. These compounds also exhibit an enhanced antiviral activity against one of the most prevalent non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant viruses that is engendered by the Y181C amino acid change in reverse transcriptase (RT). Further enhancement of activity is observed with RTs that possess the Y181C change together with AZT-resistant mutations. Moreover, when challenged with viruses containing Y181C and K103N dual mutations, calanolide compounds remain active. These dual mutations are highly resistant to all approved NNRTIs (eg, delavirdine, nevirapine and efavirenz). In cell culture assays, calanolide compounds, especially (+)-calanolide A, select primarily resistant viruses possessing the T139I amino acid change. This mutation appears to be unique to calanolides since it remains susceptible to other NNRTIs. Synergistic effects are observed in both cultured cells and animal models when calanolides are used in combination with other anti-HIV agents. Enzymatic analyses indicate that calanolides inhibit HIV-1 RT through a mechanism that affects both the Km for normal substrate dTTP and the Vmax, resulting in a mixed-type inhibition, which is different from that of other known NNRTIs. Two possible binding modes/sites at the HIV-1 RT enzyme have been suggested for (+)-calanolide A. Taken together, the calanolide compounds represent a novel and distinct subgroup of the NNRTI family and inclusion of a calanolide in a combination therapy may be clinically beneficial. Of particular interest is the use of calanolide in the treatment of patients who have failed other NNRTI therapy and developed the Y181C mutation or the Y181C/K103N dual mutations. Currently, (+)-calanolide A, the most potent in the series of calanolide compounds, is undergoing clinical investigation for safety and efficacy in HIV-infected individuals.

T R Jenta

Papers

Calanolides, the naturally occurring anti-HIV agents