Recently, Prof. Liu Xinyong & Zhan Peng's team from the School of Pharmaceutical Sciences published the latest research achievements of anti-AIDS drugs in Science Advances with the title of “Development of enhanced HIV-1 non-nucleoside reverse transcriptase inhibitors with improved resistance and pharmacokinetic profiles”. Associate Prof. Wang Zhao, Prof. Kang Dongwei, and graduate student Samuel Desta Guma of Shandong University, and Dr. Shawn Rumrill of Rutgers University are the first authors of this paper. Prof. Zhan Peng and Prof. Liu Xinyong of Shandong University, Associate Prof. Francesc Xavier Ruiz and Prof. Eddy Arnold of Rutgers University, and Prof. Chin Ho Chen of Duke University are the corresponding authors of this paper. The School of Pharmaceutical Sciences of Shandong University is the first research institution.

Viral infections seriously threaten human public health worldwide. The development of antiviral drugs is crucial for controlling and preventing viral diseases. The problem of viral drug resistance has always been a serious challenge for antiviral drug therapy, so the development of potent antiviral drugs with higher resistance profiles has become a major need in global public health. Acquired immune deficiency syndrome (AIDS) is a serious infectious disease caused by human immunodeficiency virus (HIV) infection. Currently, there are about 39.9 million HIV-infected people in the world, while about 1.355 million patients are now infected with HIV in China, and the number of newly discovered HIV infections continues to rise every year. However, most of the clinically available anti-AIDS drugs are characterized by low efficacy, serious side effects, and poor patient tolerance. Therefore, it is of great strategic significance to be guided by major clinical demands, conduct research on original drugs, and focus on promoting the development of innovative anti-AIDS drugs.

In this study, we focused on the scientific issues of drug resistance and safety of anti-HIV drugs, with the goal of “developing safe and highly effective anti-AIDS drug candidates”. By applying a rational drug design strategy based on target structures, comprehensive structural modifications were carried out on the lead compounds and approved drugs. A high-quality, focused compound library was constructed to overcome the unpredictability of flexible target allosteric binding. After anti-HIV assay, structural biology research, and preliminary druggability evaluation, 5i3 has been identified as an anti-AIDS candidate compound with excellent drug resistance and druggability profiles. Compound 5i3 exhibited highly efficient and broad-spectrum antiviral activities against HIV-1 wild-type strain and various clinically resistant strains (EC50=1.16- 18.3 nM). Notably, 5i3 was 153 times more active than rilpivirine against the clinical triple-mutant strain GH9 (K101P+K103N+V108I), and its antiviral activities against other multiple NNRTI-resistant strains were 3−28 times higher than those of etravirine and rilpivirine, being far superior to the latest generation of approved drugs etravirine and rilpivirine.

Structural biology is of great significance for understanding the mechanism of drug resistance and for designing anti-resistance drugs. In this study, we successfully cultured and resolved the crystal structure of the complex of triple mutant GH9 reverse transcriptase and small molecules for the first time. Structural biology studies have shown that 5i3 can induce pocket expansion and structural rearrangement of the binding site through the “roof-raising” effect, which allows it to form a new hydrogen-bonding network within the mutated pocket through conformational flexibility and positional adaptability, while maintaining the interaction force with the hydrophobic channel and protein-solvent interface region. Structural biology has elucidated the mechanism of action of 5i3 for its improved drug resistance profiles compared with rilpivirine, which provides a solid structural biology basis for subsequent modifications in this field.

Preliminary drug-likeness evaluation results showed that 5i3 not only exhibited good in vivo safety but also possessed excellent pharmacokinetic properties, with an oral bioavailability of 59.9%, which was significantly better than that of etravirine. It is worth mentioning that drug-selective pressure and phenotypic cross-resistance study found that 5i3 did not show cross-resistance with rilpivirine and multiple NRTI drugs, supporting a synergistic combination for antiviral therapy. Therefore, 5i3 is a high-quality drug candidate worthy of development for the future treatment of AIDS as an HAART therapy component in combination with other NRTIs.

Fig 1 Structure-based drug design and the discovery of a novel potent anti-AIDS drug candidate 5i3 with improved drug resistance profiles

In summary, based on the major clinical needs, the present work has successfully discovered a novel and potent anti-AIDS candidate compound 5i3 by utilizing the multidisciplinary design concepts of medicinal chemistry strategy, structural biology information and computer-aided drug design, which is expected to develop new anti-AIDS drugs with independent intellectual property rights and market competitiveness for our country. This research work is an extension and deepening of the anti-AIDS drug research efforts of Prof. Liu Xinyong & Zhan Peng's team over the years, and has been funded by the National Natural Science Foundation of China, the National Science and Technology Major Projects for “Major New Drugs Innovation and Development”, the Natural Science Foundation of Shandong Province, and the US National Institutes of Health grant, and other projects.