**4.6. Novel targets and synthetic molecules to inhibit active retroviral replication**

From binding to release, the replication of HIV involves several steps of which, only a few steps are targeted by the currently available anti-retroviral drugs and their congeners. As the various sub-cellular and molecular mechanisms of HIV replication are gradually being unraveled, novel compounds are also being identified to target and inhibit one or more steps of HIV replication. Most of these are small synthetic molecules identified based on computa‐ tional analysis of their structure and ability to dock at the required site and further screened for functionality by *in vitro* bioassays. As the discovery of newer anti-retroviral compounds is an ongoing process, table-3 summarizes a non-exhaustive list of novel synthetic anti-retroviral compounds and the phase of HIV replication they inhibit.


tion and could thereby reduce an extra pill. Caffeoyl-anilide compounds are evaluated for their dual action in inhibiting HIV integrase and blocking the CCR5 receptor mediated entry [23].

Certain compounds such as pharmacokinetic boosters and virostatics, are being evaluated for their role in potentiating the action of anti-retroviral drugs. The property of pharmacokinetic boosting is exclusively exploited for protease inhibitors which are metabolized and cleared from the body by the cytochrome P-450 CYP3A4 enzyme. The effect of protease inhibitors can be boosted if they are co-administered with compounds that inhibit this enzyme. The protease inhibitor ritonavir with the propensity to inhibit the cytochrome P-450 CYP3A4 enzyme, when co-administered with another protease inhibitor not only enhances its bioavailability, but also acts synergistically to minimize the dosage of both agents [24]. The combination of lopinavir boosted by ritonavir has been identified to provide maximum benefits with minimal adverse effects and hence is approved by the FDA and marketed as a fixed dose combination pill under the name, kaletra. Cobicistat is another unrelated compound which is a potent inhibitor of the cytochrome P-450 CYP3A4 enzyme without having any inherent anti-retroviral activity. As it is also capable of boosting the beneficial effects of integrase inhibitors, it is approved for use along with the fixed combination of elvitegravir, emtricitabine and tenofovir under the trade

Virostatics is an abbreviation for the combination of antiviral (viro) and cytostatic drugs (static). This combination intends to reduce viremia by inhibiting HIV replication with antiretroviral drug and simultaneously reducing the number of the viral target cells (normal CD4 T-cells), using the cytostatic drug. It has been observed that the antiviral drug didanosine functions synergistically with hydroxyurea, an inhibitor of cellular proliferation to achieve viral load reduction. As this strategy depends on hydroxyurea induced immunosuppression for reduction of viremia, more knowledge has to be gained on its practicality, with respect to didanosine resistant HIV mutants and flare-up of opportunistic infections [26, 27]. The antiparasitic / anti-inflammatory drug leflunomide is also found to have similar synergistic effect to inhibit HIV replication when used along with nucleoside reverse transcriptase inhibitors

**4.6. Novel targets and synthetic molecules to inhibit active retroviral replication**

compounds and the phase of HIV replication they inhibit.

From binding to release, the replication of HIV involves several steps of which, only a few steps are targeted by the currently available anti-retroviral drugs and their congeners. As the various sub-cellular and molecular mechanisms of HIV replication are gradually being unraveled, novel compounds are also being identified to target and inhibit one or more steps of HIV replication. Most of these are small synthetic molecules identified based on computa‐ tional analysis of their structure and ability to dock at the required site and further screened for functionality by *in vitro* bioassays. As the discovery of newer anti-retroviral compounds is an ongoing process, table-3 summarizes a non-exhaustive list of novel synthetic anti-retroviral

**4.5. Synergistic enhancers of anti-retroviral drug action**

216 Trends in Basic and Therapeutic Options in HIV Infection - Towards a Functional Cure

name, striblid [18, 25].

[28, 29].


**Table 3.** Novel synthetic anti-retroviral compounds and their mechanism of action

Although most of these compounds have shown potent *in vitro* anti-retroviral activity, their *in vivo* efficacy needs to be evaluated. A few of the listed drug candidates are undergoing clinical trials and are expected to be available for use in the near future. The concept of using antiviral compounds for treatment of HIV poses a significant drawback. Unlike other viruses, HIV possesses an immense potential to undergo genetic variation and the anti-retroviral agents rapidly select out resistant mutants. This could be well explained with the experiences faced with the experimental uncoating inhibitor PF74 and the maturation inhibitor bevirimat. The action of both these drugs can be nullified by HIV with simple mutations causing amino acid substitutions and these resistant mutants are expected to emerge rapidly if these drugs get approved for widespread use [41, 73]. While comparing the length of time and amount of work required to approve new anti-retroviral molecules acting on viral components, it is almost an instantaneous process for HIV to develop resistance against the drugs. In this context, compounds that inhibit the genetically more stable host components to produce anti-retroviral effects such as the CCR5 / CXCR4 inhibitors hold promise, until the virus finds an alternative to evade their action.
