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Phospholipid analogs are a new class of compounds with potent activity against HIV infection when used alone or conjugated with other therapeutic agents. When conjugated to the nucleoside analog AZT, the resulting phospholipid- AZT conjugate can double target the virus replication cycle by inhibiting the viral reverse transcriptase (by AZT) and inducing the production of defective virus particles that lack functional gp120 expression on the virus surface resulting in reduced capacity to bind to CD4+ cells and inhibition of infected cell-cell fusion (by phospholipid). Of great interest are data indicating that selected phospholipids are active against drug resistant variants, a current major problem in treating HIV / AIDS and controlling the epidemic occurring in various parts of the world. The purpose of this review is to provide current information on the design and synthesis of various types of phospholipids and phospholipid conjugates, in-vitro and in-vivo antiviral activity, tissue distribution, intracellular metabolism, and mechanism of action. The future development of this novel class of compounds offers an exciting approach for reducing the toxicity and enhancing the distribution of therapeutic drugs to the lymphatics and central nervous system and suppressing the emergence of drug resistant variants of HIV.

Chinese and other herbal medicines are being used increasingly by the general populations in both Eastern and Western countries, particularly as dietary supplements in the latter, to relieve and treat many different human diseases. By applying advanced scientific technology, herbal medicine can serve as a unique, fundamental basis for modern drug discovery and development. Herbal medicine must be researched and modernized in order to assure safety and efficacy, to provide qualitative and quantitative analyses for dietary supplements, and to develop new, effective, and safe world-class drugs. This drug design process is an iterative process of bioactivity-directed fractionation and isolation of natural lead compounds, chemical modification and improvement through structure-activity relationship, mechanism of action, drug metabolism, molecular modeling, and combinatorial chemistry studies, as well as efficacy and toxicity determination and clinical trials. From these studies, new drugs can be continuously generated from Chinese medicine. Importantly, now and in the future, not only bioactive lead compounds, but also active fractions and active prescriptions, must be investigated to continue the legacy of Chinese medicine for drug development in the 21st century. Such current perspectives and examples of herbal medicines and new drug development in China, Japan, the US, and other countries are illustrated in this paper.

Our laboratories first reported two novel classes of complex synthetic lipids, including alkylamidophosphocholines (PC lipid; CP-51) and alkylamidophosphate ester-linked lipid–AZT conjugates (lipid–AZT conjugates; CP-92), with selective and potent activity against human immunodeficiency virus type 1 (HIV-1). To extend these observations, we synthesized additional PC lipids and lipid–AZT conjugates (INK and INK–AZT conjugate) to evaluate their structure–activity relationships by testing for selectivity against infectious wild-type (wt) and drug-resistant HIV-1 replication, virus fusogenic activity and toxicity for mouse bone marrow cells. PC lipid compounds with medium chain lengths at positions 1 and 2 gave an improved selective index (SI). INK-3, with 12 and 8 carbons and INK-15, with 10 and 12 carbons were among the most selective when evaluated in CEM-SS cells. INK-14, a lipid–AZT conjugate where AZT replaced the choline in PC lipid INK-3, gave the highest SI of >1250 against both infectious wt HIV-1 replication in CEM-SS cells and a clinical isolate in peripheral blood leukocytes. Notably, the PC lipid compounds INK-3 and INK-15, but not the lipid–AZT conjugate INK-14, were potent inhibitors of matched pairs of AZT-sensitive and AZT-resistant HIV-1 clinical isolates. INK-3 also inhibited replication of HIV-2 and TIBO-resistant HIV-1, and inhibited HIV-1-mediated fusogenic activity by 78, 41 and 9% in a dose-dependent manner. The TC50 for mouse bone marrow cells was >100 μg/ml for INK-3 compared to 9.15–14.17 μg/ml for CP-51 and 0.142–0.259 μg/ml for AZT. These data suggest that optimum PC lipid compounds are significantly less toxic than AZT and have high potential as novel therapeutic agents for AIDS.

A series of novel boronic acid derivatives containing either a pyrimidine or purine base was synthesized. The preparation involved the condensation of 4-bromobutyl boronic acid with the appropriate base. These acyclic nucleosides were designed as potential antiviral agents especially targeting the human immunodeficiency virus. Two analogues, 6-chloro-9-(4-dihydroxyborylbutyl)purine and 2,6-dichloro-9-(4-dihydroxyborylbutyl)purine, exhibited EC50 values of 7.7 μM and 0.99 μM, respectively, in an HIV-1 syncytial plaque reduction assay.