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2750000 Shares Common Stock Use these links to rapidly review the document TABLE OF CONTENTS TABLE OF CONTENTS Table of Contents Filed Pursuant to Rule 424(b)(5) Registration No. 333-220314 PROSPECTUS SUPPLEMENT (To Prospectus Dated October 5, 2017) 2,750,000 Shares Common Stock We are offering 2,750,000 shares of our common stock, par value $0.00001 per share. In a concurrent private placement, we are also selling warrants to purchase an aggregate of 2,750,000 shares of our common stock (the "Warrants"). Each Warrant will be exercisable from the date of issuance of the common stock sold hereunder until the five-year anniversary of the date of issuance of common stock sold hereunder. 1,375,000 Warrants will have an exercise price of $10.00 per share (the "Class A Warrants") and 1,375,000 of the Warrants will have an exercise price of $15.00 per share (the "Class B Warrants"), in each case subject to adjustment. The Warrants and the shares of common stock issuable upon the exercise of the Warrants (the "Warrant Shares") are not being registered under the Securities Act of 1933, as amended (the "Securities Act"), pursuant to the registration statement of which this prospectus supplement and the accompanying base prospectus form a part nor are such Warrants and Warrant Shares being offered pursuant to such prospectus supplement and base prospectus. The Warrants are being offered under an exemption from the registration requirements of the Securities Act. The Warrants are not and will not be listed for trading on any national securities exchange. Each purchaser will be an "accredited investor" as such term is defined in Rule 501(a) under the Securities Act. Our common stock is listed on The Nasdaq Global Market under the symbol "PTGX." On August 3, 2018, the last reported sale price of our common stock was $7.01 per share. We are an "emerging growth company" under applicable Securities and Exchange Commission rules and are eligible for reduced public company disclosure requirements. See "Prospectus Supplement Summary—Company Information." Our business and an investment in our common stock involve significant risks. These risks are described under the caption "Risk Factors" beginning on page S-9 of this prospectus supplement and page 7 of the accompanying prospectus. Neither the Securities and Exchange Commission nor any state securities commission has approved or disapproved of these securities or passed upon the accuracy or adequacy of this prospectus. Any representation to the contrary is a criminal offense. Delivery of the shares of common stock will be made on or about August 8, 2018. Prospectus Supplement dated August 7, 2018 Table of Contents TABLE OF CONTENTS PROSPECTUS SUPPLEMENT Page ABOUT THIS PROSPECTUS SUPPLEMENT S-2 PROSPECTUS SUPPLEMENT SUMMARY S-4 THE OFFERING S-8 RISK FACTORS S-9 FORWARD-LOOKING STATEMENTS S-14 USE OF PROCEEDS S-15 DIVIDEND POLICY S-16 CAPITALIZATION S-17 DILUTION S-18 PRIVATE PLACEMENT TRANSACTION S-19 PLAN OF DISTRIBUTION S-20 LEGAL MATTERS S-21 EXPERTS S-21 WHERE YOU CAN FIND MORE INFORMATION S-21 INCORPORATION OF CERTAIN INFORMATION BY REFERENCE S-22 PROSPECTUS Page ABOUT THIS PROSPECTUS i SUMMARY 1 THE SECURITIES WE MAY OFFER 4 RISK FACTORS 7 FORWARD-LOOKING STATEMENTS 7 FINANCIAL RATIOS 9 USE OF PROCEEDS 9 DESCRIPTION OF CAPITAL STOCK 10 16 DESCRIPTION OF DEBT SECURITIES LEGAL OWNERSHIP OF SECURITIES 23 PLAN OF DISTRIBUTION 27 LEGAL MATTERS 30 EXPERTS 30 WHERE YOU CAN FIND MORE INFORMATION 30 INCORPORATION OF CERTAIN INFORMATION BY REFERENCE 31 S-1 Table of Contents ABOUT THIS PROSPECTUS SUPPLEMENT This document is in two parts. The first part is this prospectus supplement, which describes the specific terms of this common stock offering and also adds to and updates information contained in the accompanying prospectus and the documents incorporated by reference herein. The second part, the accompanying prospectus, provides more general information. Generally, when we refer to this prospectus, we are referring to both parts of this document combined. To the extent there is a conflict between the information contained in this prospectus supplement and the information contained in the accompanying prospectus or any document incorporated by reference therein filed prior to the date of this prospectus supplement, you should rely on the information in this prospectus supplement; provided that if any statement in one of these documents is inconsistent with a statement in another document having a later date—for example, a document incorporated by reference in the accompanying prospectus—the statement in the document having the later date modifies or supersedes the earlier statement. We further note that the representations, warranties and covenants made by us in any agreement that is filed as an exhibit to any document that is incorporated by reference herein were made solely for the benefit of the parties to such agreement, including, in some cases, for the purpose of allocating risk among the parties to such agreements, and should not be deemed to be a representation, warranty or covenant to you. Moreover, such representations, warranties or covenants were accurate only as of the date when made. Accordingly, such representations, warranties and covenants should not be relied on as accurately representing the current state of our affairs. We have not authorized anyone to provide any information other than that contained or incorporated by reference in this prospectus supplement, the accompanying prospectus or in any free writing prospectus that we have authorized for use in connection with this offering. We take no responsibility for, and can provide no assurance as to the reliability of, any other information that others may give you. This prospectus supplement and the accompanying prospectus do not constitute an offer to sell, or a solicitation of an offer to purchase, the securities offered by this prospectus supplement and the accompanying prospectus in any jurisdiction to or from any person to whom or from whom it is unlawful to make such offer or solicitation of an offer in such jurisdiction. The information contained in this prospectus supplement, the accompanying prospectus, any free writing prospectus that we have authorized for use in connection with this offering, including the documents incorporated by reference herein or therein is accurate only as of the respective dates thereof, regardless of the time of delivery of this prospectus supplement and the accompanying prospectus or of any sale of our common stock. It is important for you to read and consider all information contained in this prospectus supplement, the accompanying prospectus and any free writing prospectus that we have authorized for use in connection with this offering, including the documents incorporated by reference herein and therein, in making your investment decision. You should also read and consider the information in the documents to which we have referred you in the sections entitled "Where You Can Find More Information" and "Incorporation of Certain Information by Reference" in this prospectus supplement and in the accompanying prospectus. We are offering to sell, and seeking offers to buy, shares of our common stock only in jurisdictions where offers and sales are permitted. The distribution of this prospectus supplement and the accompanying prospectus and the offering of the common stock in certain jurisdictions may be restricted by law. Persons outside the United States who come into possession of this prospectus supplement and the accompanying prospectus must inform themselves about, and observe any restrictions relating to, the offering of the common stock and the distribution of this prospectus supplement and the accompanying prospectus outside the United States. This prospectus supplement and the accompanying prospectus do not constitute, and may not be used in connection with, an offer to sell, or a solicitation of an offer to buy, any securities offered by this prospectus supplement and the S-2 Table of Contents accompanying prospectus by any person in any jurisdiction in which it is unlawful for such person to make such an offer or solicitation. Except as otherwise indicated herein or as the context otherwise requires, references in this prospectus to "Protagonist," "the company," "we," "us," "our" and similar references refer to Protagonist Therapeutics, Inc., a corporation under the laws of the State of Delaware. S-3 Table of Contents PROSPECTUS SUPPLEMENT SUMMARY This summary highlights certain information about us, this offering and selected information contained elsewhere in or incorporated by reference into this prospectus supplement. This summary is not complete and does not contain all of the information that you should consider before deciding whether to invest in our common stock. For a more complete understanding of our company and this offering, you should read and consider carefully the more detailed information included or incorporated by reference in this prospectus supplement, the accompanying prospectus and any free writing prospectus that we have authorized for use in connection with this offering, including the factors described under the heading "Risk Factors" beginning on page S-9 of this prospectus supplement, as well as the information included in any free writing prospectus that we have authorized for use in connection with this offering. Protagonist Therapeutics, Inc. Overview We are a clinical stage biopharmaceutical company with a proprietary technology platform that enables the discovery and development of novel constrained peptide-based drug candidates that address significant unmet medical needs. Our product candidates are designed to affect critical steps in the biological pathways of particular diseases, for example, by blocking protein-protein interactions. We believe our peptide-based approach has advantages over alternative approaches such as small molecules and antibodies. Our clinical stage product candidates PTG-100 and PTG-200 are oral drugs that block biological pathways currently targeted by marketed injectable antibody drugs and offer targeted delivery to the gastrointestinal ("GI") tissue compartment.
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