Anti-Herpes Agents: Thymidine Kinase Agents – Antiviral Drugs

00:02 This slide covers the spectrum of anti herpes agents, each with unique mechanisms of action that inhibit viral replication and combat herpes virus infections. Some of these will be discussed more in depth later in this lecture. So this is just intended to give the big picture and provide a useful reference.

00:21 Thymidine kinase dependent agents like acyclovir and ganciclovir are a subset of nucleoside analogs that inhibit viral DNA polymerase after activation by viral enzymes.

00:33 They are the cornerstone therapies for herpes simplex virus (HSV) and varicella zoster virus (VSV).

00:41 These drugs are phosphorylated by viral enzymes into their active forms, where they competitively inhibit viral DNA polymerase, leading to premature termination of DNA synthesis, thereby preventing viral replication.

00:55 Pyrophosphate analogs like foscarnet are typically reserved for resistant cases of HSV and cytomegalovirus (CMV). Foscarnet directly targets the viral DNA polymerase by binding to the pyrophosphate site, hindering DNA chain elongation crucial for viral replication. Immunomodulators such as imiquimod are employed primarily against genital warts caused by HPV.

01:21 Unlike direct antiviral agents, imiquimod boosts the body's immune response by activating toll-like receptor 7 (TLR7), leading to the production of antiviral cytokines like interferon-alpha.

01:34 Non-nucleoside analogs represented by maribavir, offer an alternative for treating CMV, particularly when resistance to standard therapies emerges.

01:43 Maribavir uniquely inhibits the UL97 protein kinase of CMV, a key enzyme involved in multiple stages of viral DNA replication.

01:52 Topical Antivirals like docosanol are used for treating cold sores (herpes labialis).

01:56 This drug inhibits the fusion of fusion of the herpes virus envelope with the host cell membrane, thereby preventing the virus from entering and infecting host cells.

02:07 Host targeting agents such as leflunomide, typically used in rheumatoid arthritis, are employed off label for complex CMV syndromes, especially when conventional antiviral therapies fail.

02:20 Leflunomide disrupts virion assembly and inhibits pyrimidine synthesis, offering a different mode of action compared to standard antivirals.

02:28 Cidofovir is an acyclic nucleotide analog that requires phosphorylation by host cell kinases to form its active diphosphate metabolite, which inhibits viral DNA polymerase.

02:39 Finally, Helicase-Primase Inhibitors like pritelivir and amenamevir, though not yet FDA-approved, present a promising approach for treating resistant herpesvirus infections.

02:50 These drugs inhibit the helicase-primase complex, essential for unwinding viral DNA, effectively blocking viral replication at a different stage than traditional nucleoside analogs.

03:03 Let's explore deeper into the more commonly used medications that are active against herpes. The thymidine kinase-dependent agents include acyclovir and ganciclovir.

03:13 They're active against HSV-1 and HSV-2, as well as varicella zoster.

03:18 They have a short half life, particularly acyclovir, and are often administered 2 to 5 times a day, depending on the formulation and indication.

03:28 They are renally excreted, so we do adjust the dose in renal failure.

03:32 Let's have a look at where they work on our on our slide here.

03:36 Now as we're going through the production of DNA, we have several steps.

03:42 Acyclovir and ganciclovir are phosphorylated by viral thymidine kinase to their active triphosphate forms, which then inhibit viral DNA synthesis.

03:53 They're a competitive substrate for DNA polymerase, and they lead to chain termination after incorporation into the DNA. Because they are defective agents, because they cause a defect in the actual DNA, you're unable to continue production of the DNA chain itself.

04:13 That's why we call it chain termination.

04:15 The major adverse effects of acyclovir include acute kidney injury, neurotoxicity, and thrombotic microangiopathy.

04:23 Ganciclovir was given a US Boxed Warning for 4 conditions: hematologic toxicity, impairment of fertility, fetal toxicity, and mutagenesis and carcinogenesis. Renal toxicity is another potential adverse effect.

04:37 The U.S. Food and Drug Administration (FDA) applies boxed warnings, also known as “black box warnings”, to drugs that carry risks of severe adverse reactions, which may lead to death or serious injury.

04:50 Now, valacyclovir or Valtrex, is a prodrug of acyclovir.

04:54 So you can see here that I've placed it in a little pink box above acyclovir and ganciclovir. Now, valacyclovir is able to achieve 3 to 5 times greater concentration levels, and it also lasts a lot longer.

05:08 So for the most part, it's replaced acyclovir as a means of therapy for certain types of disease.

05:16 It has a toxicity profile similar to that of acyclovir.

05:19 Penciclovir is available only as a topical cream that works at the level of the DNA polymerase.

05:25 So it doesn’t cause chain termination. But what it does is it inhibits the production of DNA.

05:31 Now, famciclovir is given an oral formulations only and is converted to penciclovir by the liver.

05:38 So once again, I've put this prodrug form in a little pink box just under the penciclovir.

05:47 Ganciclovir is a guanine derivative.

05:50 Acyclovir is a guanosine derivative.

05:52 So you can see how they're acting at slightly different agents within the DNA molecule.

05:59 Now, when we're looking at these agents, we know that they're inhibiting DNA polymerase and cytomegalovirus and HSV alike.

06:06 They're used in CMV retinitis and other CMV infections in patients who are immunocompromised as well.

06:13 Now there is another agent that's a prodrug that I just want to mention quickly.

06:17 Valganciclovir is a prodrug of ganciclovir.

06:21 It has a very high bioavailability and a longer half-life, so it is the preferred choice in both adult and pediatric populations for the management of CMV infections. How do agents develop resistance to drugs like acyclovir? It'll occur in two different ways.

06:40 The first way is a change in the viral DNA polymerase.

06:44 So obviously, if there's a change in the target molecule, the drug won't work as well on that target molecule.

06:50 The other way that it will work is that some strains of virus actually lack the thymidine kinase that it's active upon.

06:58 So this can be a viral specific phosphorylation of acyclovir and these agents will be cross resistant to each other on these agents.

07:06 So you have to be aware that there are multiple ways of resistance and these are the two.

07:12 Let's move on to Host Kinase Agents.

07:15 Now host kinase agents are going to work on several areas of function.

07:20 But mostly we're going to be focusing on the late protein synthesis and processing of the virus. So, Cidofovir is activated by host cell kinases.

07:31 In the United States, it is only indicated for the treatment of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome (AIDS).

07:41 It was given a US Boxed Warning for Nephrotoxicity, Neutropenia, Appropriate use and concerns about carcinogenicity and teratogenicity.

07:51 The toxicity that we're most concerned about is really nephrotoxicity.

07:56 So this is this is important to monitor renal function in patients on these agents.