Recently, the Liu Xinyong / Zhan Peng team of the School of Pharmaceutical Sciences of Shandong University has made significant progress in the research of highly effective anti-HIV drugs with improved drug resistance profiles. Relevant research results have been continuously published in the top authoritative journal Journal of Medicinal Chemistry (JCR Q1) in the field of Medicinal Chemistry with the titles "Discovery of Novel Dihydrothiopyrano[4,3-d]pyrimidine Derivatives as Potent HIV-1 NNRTIs with Significantly Reduced hERG Inhibitory Activity and Improved Resistance Profiles" and "Structure-Based Design and Discovery of Pyridyl-Bearing Fused Bicyclic HIV-1 Inhibitors: Synthesis, Biological Characterization, and Molecular Modeling Studies". The more exciting thing was that both of them have been selected as the inside cover papers. Doctoral student Wang Zhaoand graduate Dr. Huang Boshiare the first authors of these two papers. Professor Liu Xinyong and Professor Zhan Peng are the corresponding authors of the two papers. Researcher Kang Dongwei is the co-corresponding author of the first paper.

HIV-1 reverse transcriptase (RT), an RNA-dependent DNA polymerase that uses single-stranded RNA templates to synthesize double-stranded viral DNA, is a validated target for AIDS therapy. Non-nucleoside RT inhibitors (NNRTIs) are widely used in combination antiretroviral therapy with the advantage of their promising antiviral activity and higher selectivity. However, the NNRTIs have a low genetic barrier, and the adverse effects have been observed after long-term treatment. Therefore, there is an urgent need of novel NNRTIs with greater potency, improved drug-resistance profiles, and safety.

The second-generation NNRTI drugs etravirine (ETR) and rilpivirine (RPV) share a common diarylpyrimidine scaffold, and show robust antiviral potency against a panel of drug-resistant strains. Nevertheless, due to the high mutation rate of HIV-1 RT and the lack of proofreading enzyme activity, resistant strains against ETR and RPV are also emerging, such as E138K and E138K+M184V/I. And both of them are suffering from poor solubility and low bioavailability. Besides, RPV can induce a dose-dependent prolongation of the QT interval that is usually closely related to severe cardiotoxicity by blocking the hERG channel. Therefore, optimizing druggability (such as increasing water solubility and improving safety) is also the main direction of the novel NNRTIs discovery program. Recent rapid development of viral structural biology has allowed the crystal structure of a large number of small molecule/target protein complexes to be resolved, providing theoretical basis for the precise target-based drug design. Recently, based on the new insights into the structural biology of NNRTI binding pocket (NNIBP), the Liu Xinyong / Zhan Peng team has carried out structural diversity modification and structure-activity relationship discussion of the lead compounds ETR/RPV by employing the "multi-site binding" and "form hydrogen bonds with key amino acid residues" drug design strategies; this program resulted in the discovery of novel dihydrothiopyrano[4,3-d]pyrimidine derivatives and pyridine-containing fused bicyclic derivatives. Among them, two compounds 20a (EC₅₀= 4.44−54.5 nM; CC₅₀= 284 μM) and 30 (EC₅₀= 1.7−319 nM; CC₅₀> 60.8 μM) proved to be exceptionally potent against a wide range of HIV-1 strains carrying NNRTI-resistant mutations. Meanwhile, the introduction of alicyclic rings greatly increased the solubility of 20a (Sol. = 12.8 μg/mL). Besides, 20a displayed no significant inhibition on main cytochrome P450 enzymes and exhibited no acute toxicity at doses of 1000 mg/kg in Kunming mice. Most importantly, the hERG inhibition profile of 20a (IC₅₀= 19.84 μM) was a remarkable improvement compared to the NNRTI drug RPV (IC₅₀= 0.50 μM), which are expected to solve the potential cardiotoxicity problem of RPV. Molecular dynamics simulations were performed in detail to achieve an in-depth understanding about the theoretical binding modes of active compounds within RT and to better elucidate the distinct anti-resistance profiles of the active compounds, which provided important clues for further molecular elaboration.

This research work has been supported by the National Science and Technology Major Projects for “Major New Drugs Innovation and Development”, National Natural Science Foundation of China, Shandong Provincial Key Research and Development Project, Science Foundation for Outstanding Young Scholars of Shandong Province, and other projects.

In recent years, the Liu Xinyong / Zhan Peng team of Shandong University has been cooperating closely with international counterparts in response to major clinical needs in the field of anti-AIDS drugs. On the one hand, the comprehensive application of structural biology, computer-aided drug design, classical medicinal chemistry strategies, and large-scalein situ click chemistry screening has led to the identification of a variety of promising anti-AIDS drug candidates with excellent potency and favorable drug-like properties. On the other hand, a series of potential lead compounds for the novel anti-AIDS targets have been discovered by employing the compound library construction, phenotypic screening, and target confirmation strategies. Related research results have been continuously published in the top journal Journal of Medicinal Chemistry (2021,64, 4239; 2020,63, 4790；2020,63, 4837; 2020,63, 1298; 2019,62, 1484; 2019,62, 2083; 2017,60, 4424; 2016,59, 7991). The anti-AIDS drug candidates discovered by the Liu Xinyong / Zhan Peng team have been transferred to Shandong Qidu Pharmaceutical Co., Ltd. for standardized preclinical evaluation, and have been funded by the National Science and Technology Major Projects for “Major New Drugs Innovation and Development”.

Meanwhile, we have summarized the distinctive perspectives and contemporary medicinal chemistry strategies formed in the development of antiviral drugs. The relevant results have been published in the top journal Chemical Society Reviews (Peng Zhan*, Xinyong Liu*,et al.2021,50, 4514.) and an English monograph (Xinyong Liu, Peng Zhan,et al.Antiviral Drug Discovery and Development,2021), which are expected to provide valuable insights for the development of new antiviral agents for major disease outbreaks.

Paper 1：Zhao Wang, Waleed A. Zalloum, Wenbo Wang, Xiangyi Jiang, Erik De Clercq, Christophe Pannecouque, Dongwei Kang*, Peng Zhan*, and Xinyong Liu*. Discovery of Novel Dihydrothiopyrano[4,3-d]pyrimidine Derivatives as Potent HIV-1 NNRTIs with Significantly Reduced hERG Inhibitory Activity and Improved Resistance Profiles.J. Med. Chem. 2021, DOI: 10.1021/acs.jmedchem.1c01015.

Paper 2：Boshi Huang, Tiziana Ginex, F. Javier Luque, Xiangyi Jiang, Ping Gao, Jian Zhang, Dongwei Kang, Dirk Daelemans, Erik De Clercq, Christophe Pannecouque, Peng Zhan*, and Xinyong Liu*. Structure-based Design and Discovery of Pyridyl-bearing Fused Bicyclic HIV-1 Inhibitors: Synthesis, Biological Characterization, and Molecular Modeling Studies.J. Med. Chem. 2021, DOI: 10.1021/acs.jmedchem.1c00987.