4 '-ethynyl nucleoside analogs: Potent inhibitors of multidrug-resistant human immunodeficiency virus variants in vitro

A series of 4 ' -ethynyl (4 ' -E) nucleoside analogs were designed, synthes ized, and identified as being active against a wide spectrum of human immun odeficiency viruses (HIV), including a variety of laboratory strains of HIV -1, HIV-2, and primary clinical HIV-1 isolates. Among such analogs examined , 4 ' -E-2 ' -deoxycytidine (4 ' -E-dC), 4 ' -E-2 ' -deoxyadenosine (4 ' -E -dA), 4 ' -E-2 ' -deoxyribofuranosyl-2,6-diamifiopurine and 4 ' -E-2 ' -deo xyguanosine were the most potent and blocked HIV-1 replication with 50% eff ective concentrations ranging from 0.0003 to 0.01 muM in vitro with favorab le cellular toxicity profiles (selectivity indices ranging 458 to 2,600). T hese 4 ' -E analogs also suppressed replication of various drug-resistant H IV-I clones, including HIV-I,,,,,, HIV-1K(65R), HIV-1(L74V), HIV-1(M41/T69S -S-G/T215Y), and HIV-1(A62V/V75I/F77L/F116Y/Q151M). Moreover, these analogs inhibited the replication of multidrug-resistant clinical HIV-1 strains ca rrying a variety of drug resistance-related amino acid substitutions isolat ed from HIV-1-infected individuals for whom 10 or 11 different anti-HIV-1 a gents had failed. The 4 ' -E analogs also blocked the replication of a non- nucleoside reverse transcriptase inhibitor-resistant clone, HIV-1(Y181C), a nd showed an HIV-1 inhibition profile similar to that of zidovudine in time -of-drug-addition assays. The antiviral activity of 4 ' -E-thymidine and 4 ' -E-dC was blocked by the addition of thymidine and 2 ' -deoxycytidine, re spectively, while that of 4 ' -E-dA was not affected by 2 ' -deoxyadenosine , similar to the antiviral activity reversion feature of 2 ' ,3 ' -dideoxyn ucleosides, strongly suggesting that 4 ' -E analogs belong to the family of nucleoside reverse transcriptase inhibitors. Further development of 4 ' -E analogs as potential therapeutics for infection with multidrug-resistant H IV-1 is warranted.