{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T15:37:23Z","timestamp":1790869043817,"version":"4.1.0"},"reference-count":151,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,9,25]],"date-time":"2023-09-25T00:00:00Z","timestamp":1695600000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>AIDS (acquired immunodeficiency syndrome) is a potentially life-threatening infectious disease caused by human immunodeficiency virus (HIV). To date, thousands of people have lost their lives annually due to HIV infection, and it continues to be a big public health issue globally. Since the discovery of the first drug, Zidovudine (AZT), a nucleoside reverse transcriptase inhibitor (NRTI), to date, 30 drugs have been approved by the FDA, primarily targeting reverse transcriptase, integrase, and\/or protease enzymes. The majority of these drugs target the catalytic and allosteric sites of the HIV enzyme reverse transcriptase. Compared to the NRTI family of drugs, the diverse chemical class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) has special anti-HIV activity with high specificity and low toxicity. However, current clinical usage of NRTI and NNRTI drugs has limited therapeutic value due to their adverse drug reactions and the emergence of multidrug-resistant (MDR) strains. To overcome drug resistance and efficacy issues, combination therapy is widely prescribed for HIV patients. Combination antiretroviral therapy (cART) includes more than one antiretroviral agent targeting two or more enzymes in the life cycle of the virus. Medicinal chemistry researchers apply different optimization strategies including structure- and fragment-based drug design, prodrug approach, scaffold hopping, molecular\/fragment hybridization, bioisosterism, high-throughput screening, covalent-binding, targeting highly hydrophobic channel, targeting dual site, and multi-target-directed ligand to identify and develop novel NNRTIs with high antiviral activity against wild-type (WT) and mutant strains. The formulation experts design various delivery systems with single or combination therapies and long-acting regimens of NNRTIs to improve pharmacokinetic profiles and provide sustained therapeutic effects.<\/jats:p>","DOI":"10.3390\/v15101992","type":"journal-article","created":{"date-parts":[[2023,9,26]],"date-time":"2023-09-26T03:53:00Z","timestamp":1695700380000},"page":"1992","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Strategies in the Design and Development of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9792-5605","authenticated-orcid":false,"given":"Murugesan","family":"Vanangamudi","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, Amity Institute of Pharmacy, Amity University Madhya Pradesh, Gwalior 474005, Madhya Pradesh, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Senthilkumar","family":"Palaniappan","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Karpagam Academy of Higher Education, Coimbatore 641021, Tamilnadu, India"},{"name":"Center for Active Pharmaceutical Ingredients, Karpagam Academy of Higher Education, Coimbatore 641021, Tamilnadu, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muthu Kumaradoss","family":"Kathiravan","sequence":"additional","affiliation":[{"name":"Dr. APJ Abdul Kalam Research Lab, SRM College of Pharmacy, SRMIST, Kattankulathur 603203, Tamilnadu, India"},{"name":"Department of Pharmaceutical Chemistry, SRM College of Pharmacy, SRMIST, Kattankulathur 603203, Tamilnadu, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3031-3377","authenticated-orcid":false,"given":"Vigneshwaran","family":"Namasivayam","sequence":"additional","affiliation":[{"name":"Pharmaceutical Chemistry, Pharmaceutical Institute, University of Bonn, 53121 Bonn, Germany"},{"name":"LIED, University of L\u00fcbeck and University Medical Center Schleswig-Holstein, Ratzeburger Allee 160, 23538 L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1146\/annurev.immunol.18.1.665","article-title":"Reservoirs for HIV-1: Mechanisms for viral persistence in the presence of antiviral immune responses and antiretroviral therapy","volume":"18","author":"Pierson","year":"2000","journal-title":"Annu. 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