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Table 1. Antiviral activity of HpVs and DpVs. For DpVs, only results for analogues withbioactivity of 50% and higher are shown% Inhibition±SEM % Inhibition±SEMX 1 Peptide HIV-1at 10 μg/mlHSV-2at 50 μg/mlX 1 Peptide HIV-1at 10 μg/mlHSV-2at 50 μg/mlGly HpV1 25.4±2.3 100.0±0.0 X 2βAla HpV2 3.5±1.5 11.3±7.1 Chg DpV20 -8.4±2.6 96.7±0.8GABA HpV3 20.4±3.5 8.5±7.9 D-Chg DpV21 -2.3±5.4 100.0±0.0Ava HpV4 43.5±2.9 8.1±5.2 X 3 X 2 = LeuAhx HpV5 57.3±2.8 94.1±4.2 Val DpV1606 79.4±2.2 16.8±3.6Ahp HpV6 60.1±1.8 96.6±1.2 Thr DpV1607 36.4±0.7 78.1±1.0Aoc HpV7 56.0±1.3 98.1±1.1 Tle DpV1609 84.1±1.0 99.5±0.5L-Pro HpV8 N.T. 99.0±1.3 Ach DpV1614 87.0±3.1 73.5±1.0D-Pro HpV9 14.7±4.6 99.2±1.3 Cpg DpV1615 96.3±0.3 99.0±0.0Idc HpV10 16.0±3.2 100.0±0.0 Chg DpV1616 97.4±0.2 99.5±0.5Oic HpV11 N.T. 10.7±0.0 His DpV1619 -20.6±5.6 50.8±0.8Tic HpV12 38.6±1.8 100.0±0.0 Tyr DpV1620 53.6±24.2 18.8±0.0Ach HpV13 14.2±1.9 100.0±0.0 Arg DpV1622 87.9±0.2 97.4±0.5L-Chg HpV14 N.T. 100.0±0.0 X 4 X 2 = Leu X 3 = IleD-Chg HpV15 37.2±2.3 85.4±3.5 Cys SH DpV1623 85.3±1.5 60.2±4.1DGK HpV16 26.2±1.7 21.7±11.3 Thr DpV1625 23.9±0.2 64.1±0.0X 2 X 5 X 2 = Leu X 3 = Ile X 4 = Cys (oxid)Val DpV9 -15.3±4.1 82.2±4.6 Mes DpV1630 88.8±1.1 98.7±1.3Ile DpV13 88.8±0.0 95.4±2.6 PEG 5 DpV1631 83.3±0.8 99.6±0.4Leu DpV16 93.4±0.2 91.3±4.6 Aoa-PEG 5 DpV1632 73.7±0.3 98.2±0.9Abbreviations: Aib - α-Aminoisobutyric acid, Chg - Cyclohexylglycine, Abu - 4-Aminobutyricacid, Ava - 5-Aminoheptanoic acid, Ahx - 6-Aminohexanoic acid, Ahp - 7-Aminoheptanoicacid, Aoc - 8-Aminooctanoic acid, Idc - (S)-Indoline-2-carboxylic acid, Oic - (S)-Octahydroindole-2-carboxylic acid, Tle – tertLeucine, Tic - (3S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylicacid, Ach - 1-Amino-1-cyclohexane-carboxylic acid, Cpg – Cyclopentylglycine,Ach - 1-Amino-1-cyclohexane-carboxylic acid, hSer - Homoserine, Nle -Norleucine, Mes - Methanesulphonyl, Aoa - Aminooxyacetic acidappears not to be crucial for activity, however the presence of cysteines in positions X 4 is.N-terminal modifications in parental molecule are generally permissive and may be used tointroduce fairly large moieties, such as PEG5 spacer. Synthesis of HpVs and DpVs is muchmore efficient than these of θ-defensins, and in the case of DpV16 can be carried outentirely on resin with final yield ~200 mg per 0.5 mM scale. Mechanistically, new peptidesmimic parental θ-defensins and bind to heptad repeat 2 (HR2) of gp41. DpV16 binds toglycoprotein D of HSV-2 (gpD2) with high affinity (Kd~400 nM), which is essential forviral entry and for cell-to-cell spread of HSV. It binds also to HR2 of gpH but not HR1, anddoes not bind to gpB. DpV16 based analogues appear to be a suitable template for newantivirals.AcknowledgmentsThese studies were supported, in part, by funds from the Adams and Burnham endowments providedby the Dean’s Office of the David Geffen School of Medicine at UCLA (P.R.) and by NIH grantsAI-052017 and AI-082623 (to A.M.C.).References1. Lehrer, R.I. Nat .Rev. Microbiol. 2(9), 727-738 (2004).2. Owen, S.M., et al. AIDS Res. Hum. Retroviruses 20(11), 1157-1165 (2004).3. Cole, A.M. Protein Pept. Lett. 12(1), 41-47 (2005).559