Inflammation, Год журнала: 2024, Номер unknown
Опубликована: Дек. 28, 2024
Язык: Английский
mBio, Год журнала: 2023, Номер 14(1)
Опубликована: Янв. 10, 2023
The SARS-CoV-2 main protease (3CLpro) has an indispensable role in the viral life cycle and is a therapeutic target for treatment of COVID-19. potential 3CLpro-inhibitors to select drug-resistant variants needs be established. Therefore, was passaged vitro presence increasing concentrations ALG-097161, probe compound designed context 3CLpro drug discovery program. We identified combination amino acid substitutions (L50F E166A L167F) that associated with >20× increase 50% effective concentration (EC50) values nirmatrelvir (PF-07321332), PF-00835231, ensitrelvir. While two single (E166A provide low-level resistance inhibitors biochemical assay, triple mutant results highest levels (6× 72×). All are significant loss enzymatic activity, suggesting reduction fitness. Structural biology analysis indicates different reduce number inhibitor/enzyme interactions while binding substrate maintained. These observations will important interpretation development clinical setting. IMPORTANCE Paxlovid first oral antiviral approved infection. Antiviral treatments often viruses. In order guide use novel antivirals, it essential understand risk characterize changes genes proteins. this work, we describe time pathway allows develop against vitro. characteristics may predictive situation. our work management COVID-19 next-generation inhibitors.
Язык: Английский
Процитировано
134
Frontiers in Public Health, Год журнала: 2023, Номер 11
Опубликована: Фев. 15, 2023
Background Since the first HIV/AIDS case appeared in 1980s, has been focus of international attention. As a major public health problem, there are epidemiological uncertainties about future HIV/AIDS. It is important to monitor global statistics prevalence, deaths, disability adjusted life years (DALYs), and risk factors for adequate prevention control. Methods The Global Burden Disease Study 2019 database was used analyze burden 1990–2019. By extracting global, regional, national data on DALYs, we described distribution by age sex, explored factors, analyzed trends Results In 2019, were 36.85 million cases (95% UI: 35.15–38.86 million), 863.84 thousand deaths 78.61–99.60 thousand), 47.63 42.63–55.65 million) DALYs. age-standardized death, DALY rates 454.32 433.76–478.59), 10.72 9.70–12.39), 601.49 536.16–703.92) per 100,000 cases, respectively. increased 307.26 304.45–312.63), 4.34 3.78–4.90), 221.91 204.36–239.47) respectively, compared 1990. Age-standardized decreased high sociodemographic index (SDI) areas. High observed low areas, while predominant Southern Sub-Saharan Africa, DALYs peaked 2004 subsequently decreased. highest 40–44 group. main affecting included behavioral risks, drug use, partner violence, unsafe sex. Conclusions disease vary region, age. access care increases across countries treatment infection improves, concentrated areas with SDIs, particularly South Africa. Regional differences should be fully considered target optimal strategies options based factors.
Язык: Английский
Процитировано
68
Drug Resistance Updates, Год журнала: 2024, Номер 73, С. 101053 - 101053
Опубликована: Янв. 26, 2024
Язык: Английский
Процитировано
20
Viruses, Год журнала: 2022, Номер 14(4), С. 841 - 841
Опубликована: Апрель 18, 2022
In RNA viruses, a small increase in their mutation rates can be sufficient to exceed threshold of viability. Lethal mutagenesis is therapeutic strategy based on the use mutagens, driving viral populations extinction. Extinction catastrophe experimentally induced by promutagenic nucleosides cell culture models. The loss HIV infectivity has been observed after passage 5-hydroxydeoxycytidine or 5,6-dihydro-5-aza-2'-deoxycytidine while producing two-fold frequency. Among approved nucleoside analogs, experiments with polioviruses and other viruses suggested that ribavirin mutagenic, although its mechanism action not clear. Favipiravir molnupiravir exert an antiviral effect through lethal mutagenesis. Both drugs are broad-spectrum agents active against viruses. incorporates into RNA, affecting G→A C→U transition rates. Molnupiravir (a prodrug β-d-N
Язык: Английский
Процитировано
43
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2022, Номер unknown
Опубликована: Июнь 7, 2022
Abstract The SARS-CoV-2 main protease (3CLpro) has an indispensable role in the viral life cycle and is a therapeutic target for treatment of COVID-19. potential 3CLpro-inhibitors to select drug-resistant variants needs be established. Therefore, was passaged vitro presence increasing concentrations ALG-097161, probe compound designed context 3CLpro drug discovery program. We identified combination amino acid substitutions (L50F E166A L167F) that associated with > 20x increase EC 50 values nirmatrelvir (PF-07321332) PF-00835231. While two single (E166A provide low-level resistance inhibitors biochemical assay, triple mutant results highest levels (6x 72x). All are significant loss enzymatic activity, suggesting reduction fitness. Structural biology analysis indicates different reduce number inhibitor/enzyme interactions while binding substrate maintained. These observations will important interpretation development clinical setting. Importance Paxlovid first oral antiviral approved infection. Antiviral treatments often resistant viruses. In order guide use novel antivirals it essential understand risk characterize changes genes proteins. this work, we describe time pathway allows develop against . characteristics may predictive situation. our work management COVID-19 next generation inhibitors.
Язык: Английский
Процитировано
42
Viruses, Год журнала: 2023, Номер 15(3), С. 647 - 647
Опубликована: Фев. 28, 2023
Current antiviral therapy research is focused on developing dosage forms that enable highly effective drug delivery, providing a selective effect in the organism, lower risk of adverse effects, dose active pharmaceutical ingredients, and minimal toxicity. In this article, drugs mechanisms their action are summarized at beginning as prerequisite background to develop relevant delivery/carrier systems for them, classified briefly discussed subsequently. Many recent studies aim different types synthetic, semisynthetic, natural polymers serving favorable matrix carrier. Besides wider view delivery systems, review focuses advances based chitosan (CS) derivatized CS carriers. its derivatives evaluated concerning methods preparation, basic characteristics properties, approaches incorporation an polymer well nanoparticulate biomedical applications context actual therapy. The degree development (i.e., study, vitro/ex vivo/in vivo preclinical testing), benefits limitations reported particular viral diseases corresponding antivirotics.
Язык: Английский
Процитировано
25
Viruses, Год журнала: 2023, Номер 15(8), С. 1732 - 1732
Опубликована: Авг. 13, 2023
Antiretroviral therapies (ARTs) have revolutionized the management of human immunodeficiency virus (HIV) infection, significantly improved patient outcomes, and reduced mortality rate incidence acquired syndrome (AIDS). However, despite remarkable efficacy ART, virologic failure remains a challenge in long-term HIV-infected individuals. Virologic refers to persistent detectable viral load patients receiving indicating an incomplete suppression HIV replication. It can occur due various factors, including poor medication adherence, drug resistance, suboptimal concentrations, interactions, factors such as emergence drug-resistant strains. In recent years, extensive efforts been made understand address order optimize treatment outcomes. Strategies prevent manage include improving adherence through education, counselling, supportive interventions. addition, regular monitoring resistance testing enables early detection facilitates timely adjustments ART regimens. Thus, development novel antiretroviral agents with potency, tolerability, profiles offers new options for experiencing failure. would also face if not managed appropriately. A solution requires comprehensive approach that combines individualized care, robust monitoring, access range drugs.
Язык: Английский
Процитировано
24
Science Advances, Год журнала: 2024, Номер 10(30)
Опубликована: Июль 24, 2024
To facilitate the detection and management of potential clinical antiviral resistance, in vitro selection drug-resistant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) against virus M
Язык: Английский
Процитировано
18
Journal of the American Chemical Society, Год журнала: 2024, Номер 146(31), С. 21401 - 21416
Опубликована: Июнь 26, 2024
Long-acting drug delivery systems are promising platforms to improve patient adherence medication by delivering drugs over sustained periods and removing the need for patients comply with oral regimens. This research paper provides a proof-of-concept development of new optimized in situ forming injectable depot based on tetrabenzylamine-tetraglycine-d-lysine-O-phospho-d-tyrosine peptoid-D-peptide formulation ((NPhe)4GGGGk(AZT)y(p)-OH). The chemical versatility peptoid-peptide motif allows low-molecular-weight be precisely covalently conjugated. After subcutaneous injection, hydrogel forms from solubilized peptoid-peptide-drug response phosphatase enzymes present within skin space. system is able deliver clinically relevant concentrations model drug, antiretroviral zidovudine (AZT), 35 days Sprague–Dawley rats. Oscillatory rheology demonstrated that formation began ∼30 s, an important characteristic reducing initial bursts. Gel continued up ∼90 min. Small-angle neutron scattering data reveal narrow-radius fibers (∼0.78–1.8 nm) closely fit via flexible cylinder elliptical model. inclusion non-native peptoid monomers D-variant amino acids confers protease resistance, enabling enhanced biostability vitro. Drug release proceeds hydrolysis ester linkage under physiological conditions, releasing unmodified form further burst. Subcutaneous administration (NPhe)4GGGGk(AZT)y(p)-OH rats resulted blood plasma 90% maximal inhibitory concentration (IC90) range (30–130 ng mL–1) days.
Язык: Английский
Процитировано
17
International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(7), С. 3659 - 3659
Опубликована: Март 25, 2024
Acquired immunodeficiency syndrome (AIDS) is an enormous global health threat stemming from human virus (HIV-1) infection. Up to now, the tremendous advances in combination antiretroviral therapy (cART) have shifted HIV-1 infection a fatal illness into manageable chronic disorder. However, presence of latent reservoirs, multifaceted nature HIV-1, drug resistance, severe off-target effects, poor adherence, and high cost restrict efficacy current cART targeting distinct stages life cycle. Therefore, there unmet need for discovery new therapeutics that not only bypass limitations but also protect body’s at same time. The main goal complete eradication purging latently infected cells patients’ bodies. A potential strategy called “lock-in apoptosis” targets budding phase cycle leads susceptibility apoptosis elimination reservoirs and, ultimately, eradication. work intends present advantages disadvantages United States Food Drug Administration (FDA)-approved anti-HIV-1 drugs as well plausible strategies design development more compounds with better potency, favorable pharmacokinetic profiles, improved safety issues.
Язык: Английский
Процитировано
15