The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac.

The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac.

The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac.

The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac.

The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac.

The in vitro anti-HIV activity and cytotoxicity of the peptide conjugates were determined both in infected and non-infected CEM-SS and MT-4 cells against HIV-1 (LAI and IIIB strain, respectively) according to published procedures. These assays were also performed on infected and non-infected TK- CEM cells.The data are collected in Tables 1 and 2 together along with data for AZT. Ester conjugates when incubated with the cells for 5 days were found to inhibit HIV replication at IC50 ranging from 6 to 140 nM in TK+ CEM-SS and from 5 to 530 nM in MT-4. Under these assay conditions, AZT inhibited HIV replication at IC50 of 14 nM (CEM-SS) and 16 nM (MT-4). As with their parent drug, none of the conjugates inhibited HIV replication in TK- CEM cells. Moreover, except for compound 5Bb, none of them was found to be cytotoxic on the three cell types. The antiviral activity level measured for these ester conjugates appeared to be correlated, to some extent, to their hydrolysis t1/2 value and hence, to the amount of AZT released during the 5 days of the experiment. Indeed, the prodrug series displaying the higher t1/2 value range, that is, the Ile-AZT series, correspond to those for which a lower HIV inhibition level was obtained. Conversely, the set of prodrug that gave a higher anti-HIV inhibition, that is, the Pro-AZT series, were those that were hydrolysed more rapidly. Moreover, the faster their hydrolysis, the closer their antiviral activity to that of free AZT. This is particularly relevant for the antiviral activities measured on MT-4 cells. However, it is noticeable that compounds Z-Phe-ProAZT (2Ac) and Qnc-Phe-Pro-Ile-AZT (2Bd), which are the most stable compounds of the series, constitute exception to this rule. Indeed, these derivatives exhibited, despite a quite high stability, a surprizingly high anti-HIV activity in CEM-SS and also in MT-4 cells for 2Ac.