HIV-1 rev

Scientists appear to have discovered a way to produce a true structure of the rare but naturally-occurring anti-HIV compound Lancilactone C from start to finish. The domino-like reaction enables the total synthesis of lancilactones and related compounds. Its non-cytotoxicity in mammals could potentially make this triterpenoid an ideal candidate for treating AIDS. Having control over how a dish is cooked is always a good idea. Taking a hint from the kitchen, scientists appear to have discovered a way to produce a true structure of the rare but naturally-occurring anti-HIV compound Lancilactone C from start to finish. Its non-cytotoxicity in mammals could make this triterpenoid an ideal candidate for treating AIDS if its biological activity were clear -- and if only it were abundant in nature. Now, a research group at Kyoto University has succeeded in creating a domino-like synthesis of Lancilactone C's unique seven-membered ring structure. "Our synthetic method revealed that the proposed structure of Lancilactone C was initially incorrect," says Chihiro Tsukano of Kyoto University's Graduate School of Agriculture. "But we successfully derived its true structure from our spectral data and understanding of its biosynthesis." In addition to this revelation, Tsukano realized that the electrocyclization -- a rearrangement reaction in organic chemistry -- used in the total synthesis also occurs in biosynthesis. Ironically, it remains a mystery of whether the proposed structure containing an unsaturated seven-membered ring might exist in nature as an analog -- or equivalent compound -- and how it might affect the expression of biological activity. Tsukano's team utilized the domino-like reaction to enable the total synthesis of lancilactones and related triterpenoids. This outcome has inspired the team to further their research in optimizing compound structures, leading to possible development of novel antivirals. The endless loop of required medication and multi-drug therapies often correlates with a lower quality of life for economically burdened patients. "Our synthetic method for Lancilactone C, with its known efficacy, may lead to developing less problematic anti-HIV drugs," concludes Tsukano.

Pictured: Gilead sign in front of building/courtesy of Tada Images/Shutterstock Tuesday, a Delaware jury ruled in favor of Gilead Sciences, finding that the company’s HIV prevention medicines Truvada (emtricitabine/tenofovir disoproxil fumarate) and Descovy (emtricitabine/tenofovir alafenamide) do not infringe on U.S. government patents and that the patents themselves are invalid in the first place. Three patent claims were at the core of the lawsuit. Jurors overwhelmingly took Gilead’s side and found that the government failed to provide enough evidence showing that patients or physicians violated these patent protections by using Truvada or Descovy for pre-exposure prophylaxis (PrEP) for HIV. Meanwhile, the jury found that Gilead had been able to show “clear and convincing evidence” that all three patent claims were invalid. Truvada is a combination of two inhibitors of the HIV-1 reverse transcriptase enzyme. It prevents the virus from integrating its genetic material into its host and replicating inside the patient’s body. The drug was first approved in 2004 for the treatment of HIV-1 and then again in July 2012 for use as PrEP. Like Truvada, Descovy combines two HIV reverse transcriptase inhibitors and works via a similar mechanistic pathway. It was first approved in 2016 for HIV treatment and won another regulatory nod in October 2019 for prevention. A month later, in November 2019, the Trump administration, through the Department of Human and Health Services (HHS), sued Gilead over these PrEP approvals. The government alleged that the drug regimen that Truvada and Descovy use was first invented and proposed for prophylaxis by CDC researchers in the early 2000s. “Gilead has received billions of dollars in revenue from HIV prevention regimens invented by HHS researchers and patented by the United States,” said Jody Hunt, the Department of Justice’s assistant attorney general for the civil division in a 2019 statement. Cancer, Inflammatory Disease Deal Also on Tuesday, Gilead announced it was acquiring private San Diego biotech XinThera but declined to disclose the deal’s financial details. The buyout will give Gilead rights to XinThera’s small molecule inhibitors targeting the PARP1 protein for oncology indications and the MK2 protein for inflammatory diseases. Both PARP1 and MK2 programs have candidates that could enter clinical trials later this year and could also be leveraged to address other conditions, with the potential for combination treatments with other molecules in Gilead’s portfolio. XinThera’s highly selective PARP1 inhibitors bypass the hematological toxicities typically seen with first-generation dual PARP1/2 inhibitors. This could potentially enable combo treatments with DNA-damaging agents such as Gilead’s own Trodelvy (sacituzumab govitecan-hziy), which delivers a toxic payload into cancer cells to induce cell death. Trodelvy was first approved in 2020 for metastatic triple-negative breast cancer. Tristan Manalac is an independent science writer based in metro Manila, Philippines. He can be reached at tristan@tristanmanalac.com or tristan.manalac@biospace.com.