On the way to fight HIV: vaccines and small molecule drugs go hand in hand

According to statistics, by the end of 2016, the cumulative number of people who died of HIV infection in the world was about 36 million, with more than 35.3 million virus carriers, and this number is increasing at the rate of 2 million new cases per year In 1987, zidovudine, the world's first drug to fight HIV infection, went on the market In the past 40 years, human efforts to fight HIV infection have never stopped Recently, new vaccines and small chemical drugs are expected to join the campaign against HIV Johnson & Johnson announced that the mosaic HIV-1 vaccine under development by its Janssen Pharmaceutical companies obtained the first clinical data Gilead Sciences announced the launch of clinical trials of HIV capsid inhibitors next year, which will be the first time such inhibitors have entered the clinical research stage Since mosaic vaccine obtained the first clinical data in 2005, Janssen's vaccine prevention department has been involved in the comprehensive preclinical / clinical HIV vaccine development program (ipcavd) supported by the National Institutes of Health (NIH) The above-mentioned approach clinical research uses a kind of vaccine based on mosaic chimeric technology, which contains immunogens from different HIV subtypes that cause HIV-1 infection all over the world These immunogens were delivered via viral vectors using Janssen's advac technology based on adenovirus serotype 26 (ad26) Therefore, the combination of virus vector and soluble protein formed the chimeric initial enhanced vaccine program: they first triggered the immune system response, and then enhanced the immune system, the ultimate goal is to produce stronger and more durable immunity Cellular immune response induced by vaccine (source: cell) in preclinical clinical studies, the scheme with mosaic mosaic vaccine proved to prevent HIV like virus infection In animal experiments with rhesus monkeys, the most effective initial enhancement program reduced the risk of exposure to infection by 94% and resulted in 66% complete protection after six exposures Approach (hiv-v-a004 / nct02315703) was conducted in the United States, Rwanda, Uganda, South Africa and Thailand It is a multicenter, randomized, parallel, placebo-controlled, double-blind clinical 1 / 2A study involving 393 healthy adults without HIV infection It is in the process of evaluating the safety, tolerance and immunogenicity of various mosaic chimeric HIV-1 vaccines All vaccine regimens seem to be well tolerated The main analysis after the third vaccination showed that most of the active vaccine programs triggered antibody responses in 100% of the study participants At almost the same time, Gilead science company announced that it is ready to officially launch the clinical trials of HIV capsid inhibitors next year, which will be the first time for such inhibitors to enter the clinical research stage Gillid said the inhibitors could be given once a month, or even once a quarter At present, the main mechanism of anti AIDS drugs is to block the role of viral enzymes, but the virus is easy to be resistant Pharmaceutical chemists have to keep updating drugs or drug combinations For example, the cocktail therapy proposed by he Dayi, a Chinese American scientist, mixes protease inhibitors with a variety of antiviral drugs, so as to reduce the resistance produced by a single drug, inhibit the replication of the virus to the maximum extent, restore some or even all of the damaged immune function of the body, and thus delay the progress of the disease In addition, in order to fight against HIV resistance, HIV capsid has become a potential target The viral genome is surrounded by a layer of protein membrane, which is called nucleocapsid, while protein membrane is called capsid The basic structure of the virus is the nucleocapsid, but some viruses are also coated with one or more layers of protein membrane or lipid membrane, such as HIV The capsid of HIV consists of 1500 capsid proteins, which are arranged into eggplant type capsid to protect the virus genome by forming hexamer and pentamer HIV can bind to cell surface receptors, then transfer the capsid to the cytoplasm of cells, thus infecting human cells Gilead's scientists want to prove that small molecular compounds can destroy the barrier and effectively prevent virus replication, hoping to weaken or even kill HIV by blocking the formation or destruction of virus capsid Pfizer's pf-3450074 (source: C & EN) was inspired by Pfizer's compound pf-3450074 After synthesizing more than 4000 compounds in six years, Gilead's team found a candidate compound gs-ca1 Its biological activity has reached PM level and its metabolic stability is good It is found that the effective time in rats can be as long as 10 weeks Gs-ca1 of Gilead (source: C & EN) compared the structure of gs-ca1 and pf-3450074 The left indole structure of pf-3450074 was optimized as tetrafluoropyrazole structure, and the right lower amide structure was modified as diaryl side chain However, based on the molecular structure of gs-ca1, it contains 8 fluorine atoms, 1 cyclopropylsulfonamide group, 1 alkynyl group and chiral cyclopropane fused ring The solubility of the compound is poor, so it can only be administered by subcutaneous injection.