Recent advances in small-molecule inhibitors targeting influenza virus RNA-dependent RNA polymerase / 药学学报

Influenza virus causes serious threat to human life and health. Due to the inherent high variability of influenza virus, clinically resistant mutant strains of currently approved anti-influenza virus drugs have emerged. Therefore, it is urgent to develop antiviral drugs with new targets or mechanisms of action. RNA-dependent RNA polymerase is directly responsible for viral RNA transcription and replication, and plays key roles in the viral life cycle, which is considered an important target of anti-influenza drug design. From the point of view of medicinal chemistry, this review summarizes current advances in diverse small-molecule inhibitors targeting influenza virus RNA-dependent RNA polymerase, hoping to provide valuable reference for development of novel antiviral drugs.

Advances in the study of new BCR-ABL kinase inhibitors / 药学学报

The oncogenic product of BCR-ABL is an abnormal tyrosine kinase that causes chronic myeloid leukemia (CML). With further research into the pathogenesis of CML, the discovery of compounds that selectively inhibit abnormal BCR-ABL tyrosine kinases is a research focus worthy of attention. The first three generations of BCR-ABL inhibitors are orthosteric inhibitors, which competitively block the binding of ABL protein tyrosine kinase to ATP and prevent it from activating downstream signals. The fourth-generation BCR-ABL inhibitors allosterically inhibit ABL protein tyrosine kinase by binding to the myristoyl pocket, providing greater selectivity and maintaining activity against drug-resistant mutations proteins. Novel drug design strategies such as proteolytic targeting chimera (PROTAC), covalent inhibitors and dual targeting inhibitors also provide new directions for the development of BCR-ABL kinase inhibitors. This paper reviews recent research advances on BCR-ABL kinase inhibitors and discusses drug design strategies for various novel BCR-ABL inhibitors.

Research progress of ProTide technology and its application in the development of antiviral drugs / 药学学报

ProTide technology is a kind of prodrug design strategy invented by the team of Christopher McGuigan. ProTides are aryloxyphosphoramidates (or aryloxyphosphonamidates) which contain a phosphorus atom combined with an amino acid ester and an aryloxy group. These prodrugs can efficiently cross the cell membrane and escape from the first rate-limiting step of phosphorylation, which afford effective solutions to the drawbacks of current nucleoside analogues. At present, ProTide technology has been extensively applied in the field of antiviral research. It has been successful in providing a number of approved drugs and clinical candidates, such as sofosbuvir and so much more, highlighting the promising future in drug discovery. This review summarizes the brief history and characteristics of ProTide technology, as well as its application in the exploration of antiviral drugs.

Recent advances of antiviral drugs based on multispecific binding strategy / 药学学报

To address the continuous emergence of drug-resistant strains of viruses and the outbreaks of novel virus infections, developing new antiviral drugs based on novel strategies has become an important and urgent research topic. In recent years, the rapidly developing multi-specific binding strategy has become a focus and been widely applied in antiviral. This review summarizes the recent progress of the multi-specific binding strategy in the antiviral field from the perspective of medicinal chemistry and discusses existing challenges as well as future opportunities for antiviral drug discovery.

Design of small molecules targeting molecular chaperone system: review and perspective / 药学学报

Molecular chaperone system, which mainly consist of heat shock proteins family and their cochaperones, is crucial for maintaining proteostasis in life. It assists in folding, maturation and ubiquitin-proteasome-mediated degradation of proteins, thus to play a key role in cell proliferation and apoptosis. Functional disorder of molecular chaperone system is highly relevant to occurrence and development of multiple diseases including cancers, autoimmune disease/inflammatory, infective diseases, neurodegenerative disease, etc. Therefore, molecular chaperone system has long been regarded as potential drug targets. In this review, we outline the progress in the design of small molecules targeting molecular chaperone system and analyze the features of small molecules with different mechanisms. Finally, we put forward expects about potential development directions for future drug design in this field.

Recent advances of small molecule inhibitors directly targeting HBV / 药学学报

Hepatitis B virus infection is a serious threat to human life and health. The approved anti-HBV drugs including interferons and nucleos(t)ide analogues have serious adverse effect, rebound phenomena after drug withdrawal, and drug resistance. And the cccDNA cannot be completely eliminated by both of them, which is the reason why a complete cure for hepatitis B cannot be achieved. Therefore, developing anti-HBV drugs directly targeting protein or nucleic acid of HBV remains a current public health priority. Based on the analysis of representative literature from the last decade, this article reviews recent developments in small molecule inhibitors directly targeting HBV from a medicinal chemistry perspective.

Recent advances in small-molecule inhibitors targeting influenza virus glycoproteins / 药学学报

Hemagglutinin and neuraminidase, two important glycoproteins on the surface of influenza virus, play a considerable role in the entry and release stage of the viral life cycle, respectively. With in-depth investigation of influenza virus glycoproteins and the continuous innovation of drug discovery strategies, a new generation of glycoproteins inhibitors have been continuously discovered. From the point of view of medicinal chemistry, this review summarizes the current advances in seeking small-molecule inhibitors targeting influenza virus glycoproteins, hoping to provide valuable guidance for future development of novel antiviral drugs.

Advances in research on small molecule regulators targeting HBV cccDNA generation and transcription / 药学学报

Hepatitis B virus (HBV) represents a significant global public health challenge. Despite the availability of several approved drugs for hepatitis B treatment, the persistence of covalently closed circular DNA (cccDNA) renders HBV eradication elusive, thereby leading to disease relapse after drug withdrawal. This paper reviews the regulatory mechanisms of cccDNA formation, transcription and replication, and summarizes the research progress of related small molecule regulators from the perspective of medicinal chemistry.

Research progress of SARS-CoV-2 main protease inhibitors / 药学学报

As a common protease with high similarity among coronavirus species, the main protease (Mpro) of SARS-CoV-2 is responsible for the catalytic hydrolysis of viral precursor proteins into functional proteins, which is essential for coronavirus replication and is one of the ideal targets for the development of broad-spectrum antiviral drugs. This paper reviews the main protease inhibitors of SARS-CoV-2, including their molecular structures, potencies and drug-like profiles, binding modes and structure-activity relationships, etc.

Universal strategies and methodologies in broad-spectrum antiviral drug discovery / 药学学报

Virus infection is a serious threat to human health and social development. The increase in pandemics caused by emerging and re-emerging viruses highlights the urgent need for broad-spectrum antivirals. In this perspective, we highlight recent case studies and summarize the universal strategies and methodologies in broad-spectrum antiviral drug discovery from common targets, common steps in viral life cycle, universal strategies, and broad-spectrum molecules, hoping to provide valuable guidance for the current and future development of antiviral drugs.

Drug discovery from viewpoint of medicinal chemists / 药学学报

Taking patient needs as the core and realizing clinical value as the guidance are the purpose and path of drug discovery. Whether the first-in-class drug or follow-on drugs are all to meet the demands of patients for drugs that are not treatable or more safe and effective. In order to realize clinical value, innovative drugs driven by basic biological research include three elements: understanding the molecular mechanism of pathogenesis; Grasping the microscopic features of the disease; clarifying the mechanism of action of drugs. The interrelation among the three is the translational medicine, and the medicinal chemistry plays an important role in the translations. That is, based on the results of basic research in biology/medicine, knowledge of the molecular mechanism of disease depends upon the establishment of various in vitro/in vivo models to find the key node and molecular regulation for the treatment of disease. Combined with the knowledge of gene deletion and variation, proteomics, epigenetics and other technologies, the molecular mechanism of disease provides multi-molecular information on the level of gene, proteins, enzymes, receptors, ion channels and signal transduction for molecular drug design. Insight into the microscopic characteristics of diseases would deepen the understanding of the molecular mechanism of the pathogenesis, as well as provide a feasible scientific path for the creation of new drugs. When the molecular mechanism of disease and the action mechanism of drugs are clarified, we have a deeper and wider understanding of the application of existing drugs (or active compounds), and may offer new ideas for drug design and application. In this translational process the medicinal chemistry plays a key role which requires medicinal chemists to break through the habitual thinking and working mode, backtracking (upstream) to basic research and its achievements and applying to the direction of creating new drugs in time, as well as paying attention to the clinical requirements (downstream) and implementing the specific content of the transformation process for the R&D of innovative drugs.

Bioinorganic chemistry strategies in antiviral drug discovery / 药学学报

Over the course of human civilization, viral infections have been a part of human life and still represent one of the heaviest burdens for human and society, with a huge devastating socioeconomic impact. Inorganic and bioinorganic chemistry have made important contributions to medical science and human health in the past half century. In this paper, we selected the representative cases in recent years, and reviewed the research progress of antiviral drug discovery from the perspective of bioinorganic chemistry.

Application of bioisostere difluoromethyl in medicinal chemistry and the research progress in its synthetic methods / 药学学报

Bioisosterism is one of the most common strategies in drug structure optimization. With the development of medicinal and organic chemistry, more and more classic and non-classical bioisosteres are used in the design of novel drugs. In recent years, fluorinated groups as a bioisostere have been paid more and more attention by pharmaceutical chemists. This paper briefly reviews the physicochemical properties, chemical preparation methods of difluoromethyl (CF2H) group, and its application in drug design to provide references for drug discovery researchers.

Lead compound optimization strategy (8) - drug transporters and related drug design strategies / 药学学报

Transporters have a great influence on the transportation and distribution of drugs in the body. On the one hand, solute carrier transporters could transport drugs into tissues and organs, which may improve the oral bioavailability or change the tissue-distribution of the drugs. On the other hand, the ATP-binding cassette could pump some drugs out of the cell, which decreases the intracellular drug concentrations and leads to drug resistance. This paper summarizes the distribution, substrate characteristics and drug design strategies of several important drug transporters, such as improving bioavailability by prodrug design, introducing acid group to improve hepatic selectivity and adjusting the polarity of compounds to decrease efflux ratio.

Lead compound optimization strategy (7) —— modification strategies for peptides / 药学学报

Most peptides have high binding affinity and good selectivity for endogenous receptors and are good lead compounds to develop into drugs. Many approved drugs are derived from the structural optimization of peptide molecules, such as the antihypertensive drug captopril and the anti-hepatitis C drug telaprevir. At present, the main problems in the development of peptide drugs include poor stability, short half-life, and high plasma clearance rate; lack of oral availability and poor patient compliance, a complex production process, and high production cost. Therefore, rational modification of peptides can not only reduce the production cost, but also improve the druggability of the peptides. Here we review structural modification strategies for peptides from the perspective of improving their physicochemical properties. These modification strategies are divided into two parts: one is modification of the peptide backbone, including unnatural amino acid modification, pseudopeptide strategy, inverse-peptide strategy, cyclization strategy, and terminal structure modification. Another is modification of the side chains of peptides, including fatty acid conjugation, polyethylene glycol conjugation, protein fusion strategy, and cholesterol conjugation.

Exploring potential affected site for the inhibition of Aβ42 polymerization based on Asn27 deamidation modification / 药学学报

One of pathological features of Alzheimer's disease (AD) is extracelluar aggregation of amyloid-β protein (Aβ) forming senile plaques. Investigation on inhibition of Aβ aggregation can be crucial for designing effective drugs against AD. Previous studies have demonstrated that the deamidation at Asn27, a type of post translation modification, significantly prevented the polymerization of Aβ monomers. But the underlying mechanism is still unclear. Therefore, we investigated the possible effect of Asn27 deamidation on structure and aggregation of Aβ42 monomer using molecular dynamics simulation. The results showed that the deamidation of Asn27 can directly disrupt the salt bridge formed between D23 and K28, and effectively decrease the content of β-sheet that is important for aggregation of Aβ. Moreover, the inability at C-terminal region (CTR) and N-terminal region (NTR) to form antiparallel β-sheets further weakens the intra-peptide interaction of Aβ42 monomer. These changes caused by Asn27 deamidation lead to the decline of the aggregated trend of Aβ42 monomer, which is consistent with the experimental observation. According to these results, the salt bridge formed between D23 and K28 plays an important role in promoting the polymerization process between Aβ42 monomers, and disrupting this interaction may be a potential direction for further designing drugs to inhibit aggregation of Aβ42. In summary, this study shows a potential affected site that can efficiently inhibit aggregation of Aβ42.

Medicinal chemistry strategies in seeking coronavirus inhibitors / 药学学报

The epidemic caused by coronavirus poses a serious threat to human health, but there is no specific drug or vaccine for the treatment of this kind of virus infection. Herein, this article selects typical case studies in recent years and reviews the medicinal chemistry strategies of anti-SARS-CoV, MERS-CoV and other coronavirus drugs from the perspective of medicinal chemistry, and tries to provide some clues to current drug research againstSARS-CoV-2.

Research progress on the West Nile virus inhibitors / 药学学报

West Nile virus is a flavivirus transmitted by culex mosquitoes. People are generally susceptible to it, West Nile virus infection can cause west Nile fever, which can develop West Nile viral encephalitis and even lead to death. There are currently no approved specific antiviral drugs against West Nile virus. Therefore, seeking effective West Nile virus inhibitors is a hot topic in current community of medicinal chemistry. In this article, based on the main targets of West Nile virus, we summarize the new progress research on West Nile virus inhibitors.

New advances in the discovery of anti-enterovirus-71 agents / 药学学报

In recent years, enterovirus infection has become a frequent epidemic and developed into an important public health problem. For example, hand-foot-mouth disease has become a common infection among children in China. Hand-foot-mouth disease (HFMD) has been spreading globally since 1997, especially in the Asia-Pacific region. Enterovirus 71 (EV71) is one of the main pathogens causing HFMD. And now there is no drug available to treat EV71 infection. This review summarizes the research progress of anti-enterovirus-71 drugs from the perspective of medicinal chemistry.

New progress in medicinal chemistry of anti-poxvirus drugs research / 药学学报

Poxvirus is the largest and most complex virus of the known virions, and the main pathogenicity to humans is Orthopoxvirus. In recent years, with the deep understanding of the biological structure and replication cycle of Orthopoxvirus, new small molecular compounds with high efficiency and low toxicity have been discovered as new drugs, and some have entered the clinical trial stage. This article summarizes the research progress of poxvirus inhibitors with different targets.