Development of a Designer Proline-rich antimicrobial peptide Chaperone protein inhibitor (DPC) for treating sepsis

开发用于治疗脓毒症的富含脯氨酸的抗菌肽伴侣蛋白抑制剂 (DPC)

• 批准号: 10007300
• 负责人: Carl Neil Kraus
• 金额: $ 30万
• 依托单位: ARREVUS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-21 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10007300
• 关键词: Address; Adjuvant Therapy; Adrenal Cortex Hormones; Agonist; Animals; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Azithromycin; Bacterial Infections; Bacterial Model; Bacterial Proteins; Binding; CD28 gene; CD3 Antigens; Catabolism; Cessation of life; Chronic; Chronic stress; Colistin; Critical Illness; Data; Development; Disease; Dysplasia; Elderly; Evaluation; Exhibits; Experimental Models; Functional disorder; Goals; Guidelines; Heat shock proteins; Homologous Gene; Hospitals; Human; Imipenem; Immune; Immune response; Immunity; Immunologics; Immunosuppression; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Insecta; Interferons; Lead; Life; Liquid substance; Measurement; Measures; Mechanical ventilation; Medical; Membrane Lipids; Modeling; Molecular Chaperones; Multi-Drug Resistance; Multiple Bacterial Drug Resistance; Mus; Natural Immunity; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Peritonitis; Pharmaceutical Preparations; Phase; Plasma; Populations at Risk; Positioning Attribute; Production; Program Development; Proline; Property; Proteins; Recovery; Resuscitation; Safety; Sepsis; Small Business Technology Transfer Research; Splenocyte; Stress; Supportive care; Survivors; Syndrome; T-Lymphocyte; TNF gene; Therapeutic; Therapeutic Intervention; Treatment Efficacy; Treatment Failure; Whole Blood; adaptive immune response; adaptive immunity; antimicrobial; antimicrobial drug; antimicrobial peptide; bacterial resistance; blood product; cecal ligation puncture; cytokine; drug resistant pathogen; effective therapy; immunoregulation; immunosuppressed; improved; in vivo; inhibitor/antagonist; monocyte; mortality; mouse model; multi-drug resistant pathogen; novel; novel strategies; novel therapeutics; organ injury; pathogenic bacteria; peripheral blood; phase 2 study; polymicrobial sepsis; pre-clinical; programs; protein folding; response; septic patients; systemic inflammatory response; treatment risk; treatment strategy

PROJECT SUMMARY Sepsis is a life-threatening syndrome that involves a systemic inflammatory response that is initiated by an infection. There are an estimated 1.5 million of cases annually in the US with 250,000 resulting in death. The number of cases and associated deaths is expected to increase given the rising at-risk population of elderly individuals and the compounding challenge of antibiotic resistance. Treatment of sepsis involves antimicrobial therapy in addition to several supportive care measures to address the complications of the systemic inflammatory response. In order to effectively and appropriately address the pathophysiological aspects of sepsis, a treatment must provide antimicrobial activity in addition to immunomodulatory properties. It is imperative that efforts to identify new and effective treatment strategies for sepsis shift from the traditional antibiotic development programs that focus solely on antimicrobial activity and turn toward strategies that address both antimicrobial and immunomodulatory aspects of the disease. Arrevus is developing a novel approach to addressing sepsis using Designer Proline-rich Antimicrobial peptide Chaperone protein inhibitors (DPCs), derived from insects and selectively modified, acting as inhibitors to one of the critical bacterial proteins responsible for bacterial protein folding, DnaK. As an adjuvant therapy to current antibiotics, DPCs have the potential to provide a much-improved treatment option for multi-drug resistant (MDR) bacterial infections. Preliminary studies have displayed the potential of ARV-1502, the lead DPC, as an effective antimicrobial agent against MDR bacterial pathogens in addition to providing immunomodulatory effects. Specifically, our efforts have shown that: 1) DPCs show efficacy against MDR pathogens (both gram-negative and gram-positive) alone and in combination with traditional antibiotics; 2) DPCs offer a novel and specific bacterial target; 3) ARV-1502 has demonstrated immunomodulatory properties; and 4) ARV-1502 exhibits a favorable safety profile. Collectively, these data support the continued development of ARV-1502 through an STTR Phase I program targeting proof-of-concept data for the use of ARV-1502 in the treatment of sepsis. In this Phase I proposal, we will build upon significant preliminary data to demonstrate proof-of-concept for the use of ARV-1502 for treating sepsis through two aims. In Aim 1, we will characterize the effect of ARV- 1502 treatment on host innate and adaptive immunity using peripheral blood monocytes and T-cells from sepsis patients. In Aim 2, we will assess the in vivo efficacy of ARV-1502 in murine sepsis models to improve survival (in aim 2A using a near-lethal sepsis model) and host protective immunity (in aim 2B using a survivable murine sepsis model in which animals survive the initial infection but are immunosuppressed). The overall goal of this Phase I program is to generate initial proof-of-concept data and to assess when and how ARV-1502 would be best utilized in sepsis.

项目摘要 脓毒症是一种危及生命的综合征，其涉及全身性炎症反应， 感染据估计，美国每年有150万例病例，其中25万例导致死亡。的 由于老年高危人群不断增加， 个体和抗生素耐药性的复合挑战。脓毒症的治疗涉及抗菌药物 除了几种支持性护理措施外，还可以进行治疗，以解决全身性并发症。 炎症反应。为了有效和适当地解决的病理生理方面的 对于脓毒症，治疗必须提供除免疫调节性质之外的抗微生物活性。是 当务之急是努力确定新的和有效的治疗策略，脓毒症从传统的 抗生素开发计划只关注抗菌活性，并转向 解决疾病的抗微生物和免疫调节方面。 Arrevus正在开发一种使用富含脯氨酸的设计师抗菌剂来解决败血症的新方法 肽伴侣蛋白抑制剂（DPC），来源于昆虫并选择性修饰，用作抑制剂 一种负责细菌蛋白质折叠的关键细菌蛋白质，DnaK。作为辅助疗法用于 目前的抗生素，DPC有可能为多药治疗提供一个大大改善的治疗选择。 耐药（MDR）细菌感染。初步研究显示了ARV-1502的潜力， DPC作为一种有效的抗MDR细菌病原体的抗菌剂，除了提供 免疫调节作用。具体来说，我们的努力已经表明：1）DPC对MDR显示出功效 病原体（革兰氏阴性和革兰氏阳性）单独和与传统抗生素组合; 2） DPC提供了一种新的和特异性的细菌靶点; 3）ARV-1502已证明具有免疫调节作用 4）ARV-1502具有良好的安全性。总的来说，这些数据支持持续的 通过STTR第一阶段计划开发ARV-1502，目标是使用概念验证数据， ARV-1502治疗败血症 在本第一阶段提案中，我们将以重要的初步数据为基础，证明以下方面的概念验证： ARV-1502通过两个目的用于治疗脓毒症的用途。在目标1中，我们将描述抗逆转录病毒药物的作用- 1502使用外周血单核细胞和T细胞对宿主先天性和适应性免疫的治疗 败血症患者在目标2中，我们将评估ARV-1502在鼠脓毒症模型中的体内功效，以改善ARV-1502的体内毒性。 存活（在目的2A中，使用近致死性脓毒症模型）和宿主保护性免疫（在目的2B中，使用 可存活的鼠脓毒症模型，其中动物在初始感染中存活但免疫抑制）。的 第一阶段计划的总体目标是生成初步的概念验证数据，并评估何时以及如何进行 ARV-1502最好用于脓毒症。