New designs for HIV-1 integrase inhibitors: a patent review (2018-present)

ABSTRACTIntroduction Combination antiretroviral therapy (cART) has dramatically reduced morbidity and mortality of HIV-1-infected patients. Integrase strand transfer inhibitors (INSTIs) play an important role as a key drug in cART. The second-generation INSTIs are very potent, but due to the emergence of highly resistant viruses and the demand for more conveniently usable drugs, the development of ‘third-generation’ INSTIs and mechanistically different inhibitors is actively being pursued.Areas covered This article reviews the patents (from 2018 to the present) for two classes of HIV-1 integrase inhibitors of INSTIs and integrase-LEDGF/p75 allosteric inhibitors (INLAIs).Expert opinion Since the approval of the second-generation INSTI dolutegravir, the design of new INSTIs has been mostly focused on its scaffold, carbamoylpyridone (CAP). This CAP scaffold is used not only for HIV-1 INSTIs but also for drug discoveries targeting other viral enzymes. With the approval of cabotegravir as a regimen of long-acting injection in combination with rilpivirine, there is a growing need for longer-acting agents. INLAIs have been intensely studied by many groups but have yet to reach the market. However, INLAIs have recently been reported to also function as a latency promoting agent (LPA), indicating further development possibilities.KEYWORDS: AIDScabotegravircarbamoylpyridonedolutegravirHIV-1INLAIsINSTIsintegraseLEDGF/p75long-acting drugs Article highlights There are two classes of HIV-1 integrase inhibitors: INSTIs that chelate two divalent metal ions in the active center and INLAIs that bind to allosteric sites of the enzyme.Since the approval of the second-generation INSTI dolutegravir, its scaffold CAP has been used as a ‘universal template’ for many novel inhibitor designs for INSTIs.The CAP scaffold is also used in research to find inhibitors against other viral enzymes that have divalent metal ions in their active centers.The need for long-acting anti-HIV-1 agents has increased since the positive clinical results reported for cabotegravir.Although INLAIs are not yet on the market, they have been reported to have another function called LPA, indicating further development possibilities.This box summarizes key points contained in the article.Declaration of interestsAll authors are employees of Shionogi & Co., Ltd. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Author contribution statementY. Taoda proposed, guided, and drafted this manuscript. S. Sugiyama and T. Seki drafted and edited the manuscript.Additional informationFundingThis paper was not funded.