HIV-1 integrase inhibition

Di-caffeoylquinic acid (70) Cyclic polyolic derivative 1,5-DCQA(70) Antiviral (Anti-HIV HIV/AIDS and hepatitis B) Inhibits HIV-1 integrase Phase l/Il Chinese Academy of Military Medical Sciences 583-585... 

The first examples of marine sterols with the sulfamate ester functionality were haplosamates A and B (462 and 463), which were obtained from two sponges from the Philippines, a Xestospongia sp. (Haplosclerida, Petrosiidae) and an unidentified haplosclerid sponge [355]. The structures of haplosamates A and B were determined by interpretation of spectral data and the compounds were found to inhibit HIV-1 integrase with IC50 values of 50 pg/ml and 15 ig/ml, respectively. 

They are generally active at the two steps of the integration but are not selective for IN and the practical utility of those catechol-containing inhibitors is severely reduced by cytotoxicity even though they have been found to inhibit HIV-1 integrase in vitro. Nevertheless, lithospermic acids, Fig. (19) were found to be active on purified IN as well as on HIV-1 infected H9 cells, and showed no cytotoxicity to H9 cells [80]. 

Rajamaki et al. [36] have reported a novel series of rhodanine derivatives inhibiting HIV-1 integrase using virtual screening techniques. The compound XXXIII has displayed highest therapeutic index (7.0) of all the synthesized derivatives. 

Mitchell, S.S., Rhodes, D., Bushman, F.D., and Faulkner, D.J. (2000) Cydodidemniserinol trisulfate, a sulfated serinolipid from the Palauan ascidian Dide-mnum guttatum that inhibits HIV-1 integrase. Org. Lett., 2, 1605-1607. 

Underwood M, Harvey R, Stanat S, Hemphill M, Miller T, Drach J, Townsend L, Biron K (1998) Inhibition of human cytomegalovirus DNA maturation by a benzimidazole ribonucleoside is mediated through the UL89 gene product. J Virol 72 717-725 Van Maele B, Debyser Z (2005) HlV-1 integration an interplay between HIV-1 integrase, cellular, and viral proteins. AIDS Rev 7 26 3... 

Inhibition of HIV-1 Integrase 3 Processsing (3 -Proc), Strand Transfer (ST) and HIV-1RF Cytopathicity (HIV-1rf) by Some Guanine Quartets in Cell Cultures... 

Table 1 Representative Inhibitors of HIV-1 Integrase and IC50 values of compounds that inhibit 3 processing and strand transfer activities of HIV-1 integrase...

Several studies published since March 1996 have expanded the list of in vitro integrase inhibitors effective at IC50 values below 100 pM. These include two dicaffeoylquinic acids obtained from medicinal plants and a synthetic analog, L-chicoric acid [68], the HIV protease inhibitors NSC 117027 and NSC 158393 [69], certain anthraquinone derivatives [70], coumermycin, and pyridoxal phosphate [71]. In addition to exhibiting in vitro inhibition, the dicaffeoylquinic acids effectively inhibited HIV-1 replication in T-lymphoblastoid cell lines [68]. 

Fesen MR, Pommier Y, Leteurtre F, Hiroguchi S, Yung J, Kohn KW. Inhibition of HIV-1 integrase by flavones, caffeic acid phenethl ester (CAPE) and related compounds. Biochem Pharmacol 1994 48 595-608. 

In a related study [98], 1,5-, 3,4- and 4,5-DCQAs have been tested for inhibition of HIV-1 integrase in vitro and inhibition of HIV-1 replication in tissue culture. The activities of DCQAs against HIV-1 integrase are less than 1 pM. Indeed, all of DCQAs have been found to inhibit HIV-... 

The CAP have been reported to inhibit HIV type 1 (HIV-1) integrase and HIV-1 replications at concentrations as low as 10 p,M (McDougall et al., 1998 King et al., 1999 Reinke et al., 2002). Cichoric acid inhibited 50% of the integrase activity and blocked HIV-1 infections by 50% at concentrations of 0.3 and 4 p,M, respectively (Robinson et al., 1996a,b). Hexane extracts of Echinacea roots were found to have antiviral activity against the Herpes simplex virus type 1 at a 0.12 mg/ml concentration (Binns et al., 2002d). 

Reinke, R., King, P., Victoria, J., McDougall, B., Ma, G., Mao, Y., Reinecke, M., and Robinson, W. 2002. Dicaffeoyltartaric acid analogues inhibit human immunodeficiency virus type 1 (HIV-1) integrase and HIV-1 replication at nontoxic concentrations. J. Med. Chem. 45, 3669-3683. 

Sarcandra hainanensis (Pei) Swamy et Bailey (whole plants) Two flavan-chalcone dimers two flavan-flavanone dimers. The flavan-chalcone dimers showed HIV-1 integrase inhibition activities (IC50 = 18.05 and 25.27 pM, respectively). Cao et al., 2009[167], 2010[168]. 

Saiz-Urra, L., Perez Gonzalez, M., Fall, Y. and Gomez, G. (2007) Quantitative structure-activity relationship studies of HIV-1 integrase inhibition. 1. GETAWAY descriptors. Eur. J. Med. Chem., 42, 64-70. 

K Pfeifer, H Merz, R Stefen, WEG Muller, S Trumm, J Schulz, E Eich, HC Schroder. In-vitro anti-HIV activity of lignans- differential inhibition of HIV-1 integrase reaction, topoisomerase activity and cellular microtubules. J Pharm Med 2 75-97, 1992. 

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